WO2026024674A1 - Methods of treating skp2-associated cancers - Google Patents

Abstract

The present application relates to methods of treating SKP2-associate cancers, as defined herein, by administering one or more CDK2 inhibitors.

Description

Attorney Docket No.49366-0051WO2 METHODS OF TREATING SKP2-ASSOCIATED CANCERS RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Appl. No.63/673,973, filed on July 22, 2024, which is hereby incorporated by reference in its entirety. FIELD This present application relates to methods of treating SKP2-associated cancers by admininstering one or more CDK2 inhibitors. BACKGROUND CDKs perform essential functions in regulating eukaryotic cell division and proliferation. The cyclin-dependent kinase catalytic units are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified. See Johnson, et al., Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312. Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, and likely other heterodynes regulate cell cycle progression. Additional functions of cyclin/CDK heterodynes include regulation of transcription, DNA repair, differentiation and apoptosis. See Morgan D.O., Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291. Overexpression of CDK2 is associated with abnormal regulation of cell-cycle. The cyclin E/CDK2 complex plays and important role in regulation of the G1/S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of Rb by cyclin E/Cdk2 releases the G1 transcription factor, E2F, and promotes S-phase entry. Activation of cyclin A/CDK2 during early S-phase promotes phosphorylation of endogenous substrates that permit DNA replication and inactivation of E2F, for S-phase completion. See Asghar et al., Nat. Rev. Drug. Discov. 2015; 14(2): 130-146. Amplification or overexpression of cyclin A (CCNA2) is known to be involved in several cancer types, including breast, liver, lung, and cervical. See, e.g., Yam et al., Cell Mol. Life Sci. 2002; 59, 1317-1326 and Burkholm et al., Int. J. Cancer, 2001; 93(2) 283-287. Increased activity of cyclin A is also associated with poor clinical prognosis in non-small cell lung cancer. See Volm, et al., Br. J. Cancer, 1997; 75(12) 1774-1778. Similarly, Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells. See Caldon et al., Mol. Cancer Ther. 1 Attorney Docket No.49366-0051WO2 (2012) 11:1488-99; Herrera-Abreu et al., Cancer Res. (2016) 76: 2301-2313. The primary function of the ubiquitin–proteasome system (UPS) is to regulate the degradation and function of substrate proteins. The UPS activates and transfers the small protein ubiquitin to target proteins through the concerted action of ubiquitin-activating enzyme, ubiquitin- conjugating enzyme, and ubiquitin ligase, which are commonly abbreviated as E1, E2, and E3, respectively; this process is known as ubiquitination. Polyubiquitin chains are formed when multiple ubiqutins are linked to an existing ubiquitin on the substrate protein. Polyubiquitination of a protein targets the substrate to the proteasome for degradation. RING E3 ligases represent the most diverse group of ubiquitin ligases, and SCF RING E3 complexes in particular play a critical role in cell cycle regulation. SCF complexes are composed of Cullin 1 proteins, RING box proteins such as the adaptor protein S-phase kinase-associated protein 1 (SKP1), and members of the substrate receptor F-box protein family such as S-phase kinase-associated protein 2 (SKP2). SKP2 is a member of the ubiquitin-proteasome system that plays a role in regulating various biological processes. Wang, et al., Front. Oncol. Vol.1, pp.1-10 (2012). SKP2 is one of the components of the SCF E3 ligase complex that target selected proteins for destruction by the 26S proteasome. Frescas and Pagano, Nat. Rev. Cancer Vol.8, pp.438-449 (2008). While SKP2 has S-phase promoting function and is implicated in the ubiquitin-mediated proteolysis of the cyclin-dependent kinase (CDK) inhibitor p27, it is also involved in the ubiquitination and degradation of other cell cycle regulatory proteins, including cyclin E and E2F- 1. Gstaiger, et al., PNAS Vol.89, No.9, pp.5043-5048 (2001). Indeeed, SKP2 can ubiquitinate various cell cycle regulators and induce their proteolysis, including the CDK Kinase Inhibitors (CKIs) p21, p27, and p57. Degradation of these CDK inhibitors increases the activity of Cyclin E and Cyclin A CDK2 complexes, thereby promoting the progression of the cell cycle and cell growth and division. SKP2 deletion has been shown to increase expression of CKI proteins and decrease expression of cyclin E/A and CDK2. This results in cell cycle arrest in the G1/S phase. SKP2 copy number amplification is also common in multiple solid tumor types including non-small cell lung cancer, small cell lung cancer, esophageal cancer, bladder cancer and others. SKP2 amplified tumors where the CKIs are downregulated and cyclin E/A-CDK2 activated may be predisposed to an efficacious response to small molecule inhibition by a CDK2 inhibitor. 2 Attorney Docket No.49366-0051WO2 SUMMARY The present disclosure is based, in part, on the surprising and unexpected discovery that certain cancers, e.g., SKP2-associated cancers, are particularly vulnerable to CDK2 inhibition. Inhibition of CDK2 can result in reduction of RB phosphorylation and subsequently G1 cell cycle arrest and senescence when CCNE1 is amplified. Inhibitors of CDK2 can also result in the reduction in phosphorylation of DNA synthesis/DNA repair machinery (e.g., NCL, XRCC1, CDC6) and subsequently S-phase cell cycle arrest when SKP2 is amplified. The present disclosure demonstrates that cells grown in vitro with SKP2 amplification experience potent antiproliferative effects from CDK2 inhibition and these in vitro data are manifest as tumor regressions when cells are grown in vivo as mouse xenografts. Some embodiments provide a method for treating a SKP2-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer is a SKP2-associated cancer. Some embodiments provide a method for treating a SKP2-associated cancer in a subject in need thereof, comprising: (a) identifying the cancer as being a SKP2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for treating a cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the subject has previously been identified or diagnosed as having a SKP2-associated cancer. Some embodiments provide a method of treating a SKP2-associated cancer, comprising administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, to a subject previously identified or diagnosed as having a SKP2-associated cancer. Some embodiments provide a method for treating cancer in a subject in need thereof, 3 Attorney Docket No.49366-0051WO2 comprising: (a) determining that the cancer is associated with a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for inhibiting metastasis in a subject having a SKP2- associated cancer, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. Some embodiments provide a method for inhibiting SKP2 activity in a mammalian cell, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. Some embodiments provide a method for inducing apoptosis in a mammalian cell, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION Definitions The term “about,” when applied to a specific value or range, refers to ±10% of the specified 4 Attorney Docket No.49366-0051WO2 value or range, e.g., to account for experimental variance. The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer. The following are examples of included tautomeric forms: . It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form. The term “halogen” refers to one of the halogens, group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine. The term “alkyl” refers to a linear or branched hydrocarbon chain containing from 1-20 carbon atoms. The alkyl group may be denoted as, for example, a C1-12 alkyl group, which contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Examples of a C1-C6 alkyl group 5 Attorney Docket No.49366-0051WO2 include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The term “alkylene” refers to an alkyl group, as defined herein, which is a biradical and is connected to two other moieties. Non-limiting examples of alkylene groups include: methylene (-CH₂-), ethylene (-CH₂CH₂-), propylene (-CH₂CH₂CH₂-), isopropylene (IUPAC: (methyl)ethylene) (-CH2-CH(CH3)-), and isobutylene (IUPAC: 2-(methyl)propylene) (-CH2- CH(CH3)-CH2-). Alkylene groups can optionally include a C3-C4 cycloalkyl, as defined herein, that shares a carbon atom with the backbone of the alkylene chain, for example . The term “haloalkyl” refers to an alkyl group, as defined herein, substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C3 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloroethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2- trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2- trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The term “alkoxy” refers to an alkyl group, as defined herein, which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n- hexoxy. As used herein, the term “aryl” refers to a 6–10 all carbon mono- or bicyclic group wherein at least one ring in the system is aromatic, i.e., a C6-C10 aryl. Non-limiting examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl. In bicyclic ring systems where only one ring is aromatic, the non-aromatic ring can be a cycloalkyl group, as defined herein. As used herein, the term “heteroaryl” refers to a 5–10 membered mono- or bicyclic group wherein the ring system is aromatic; wherein one or more carbon atoms in at least one ring in the system is/are replaced with an heteroatom independently selected from N, O, and S. Heteroaryl groups include rings where one or more groups are oxidized, such as a pyridone moiety. Non- limiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, imidazole, and indole. As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated 3-10 6 Attorney Docket No.49366-0051WO2 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl. The term “heterocyclyl” refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, that is not aromatic, having at least one heteroatom within the ring selected from N, O and S. In bicyclic ring systems, one ring can be aromatic. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. The heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members. The heterocyclyl group may be denoted as, for example, a “5-10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazoline S,S-dioxide, and decahydronaphthalenyl. The term “hydroxyl” refers to an –OH moiety. The term “cyano” refers to a –CN moiety. As used herein, the term “oxo” refers to an “=O” group attached to a carbon atom. As used herein, an asterisk (*) depicts the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule. CDK2 inhibitors, such as those described herein, can include pharmaceutically acceptable salts thereof. The term “pharmaceutically acceptable” indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith. Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to ¹H, ²H, ³H or mixtures thereof; when carbon is mentioned, it is understood to refer to ¹¹C, ¹²C, ¹³C, ¹⁴C or mixtures thereof; when nitrogen is mentioned, it is understood to 7 Attorney Docket No.49366-0051WO2 refer to ¹³N, ¹⁴N, ¹⁵N or mixtures thereof; when oxygen is mentioned, it is understood to refer to ¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium (²H). As some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. The ability of selected compounds to act as CDK2 inhibitors may be demonstrated by the biological assays described herein or other similar assays to measure CDK2 inhibitory activity or designed to test similar activity and/or binding. The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a SKP2-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular SKP2- associated cancer, and/or (iii) delay the onset of one or more symptoms of the particular SKP2- associated cancer described herein. A therapeutically effective amount can have the effect of, for example, reducing tumor size, inhibiting tumor growth, inhibiting cancer cell invasiveness, inhibiting metastasis, or a combination of any of the foregoing. The amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also 8 Attorney Docket No.49366-0051WO2 mean prolonging survival as compared to expected survival if not receiving treatment. As used herein, the term “subject” refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the cancer to be treated. In certain embodiments, compounds of Formula (I), or a pharmaceutically acceptable salt thereof are useful for preventing diseases and disorders as defined herein. The term “preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof. The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA). The term “SKP2-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a SKP2 gene, a SKP2 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a SKP2 gene, a SKP2 protein, or the expression or activity or level of any of the same described herein). In some embodiments, a dysregulation can be a dysregulation that results in aberrant activation of a gene, protein, or expression or activity or level of any of the same. Activation can be through any appropriate mechanism, including, but not limited to, gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic alteration, and/or overexpression of the protein product of the oncogene. Typically, as used herein, a dysregulation results in aberrations in the cell cycle and/or disruption of normal protein degradation processes, and/or signal termination pathways. Non-limiting examples of a SKP2-associated cancer are described herein. An exemplary sequence of human CDK2 is shown below: SEQ ID NO: 1 (UniProt Accession No. P24941) MENFQKVEKIGEGTYGVVYKARNKLTGEVVALKKIRLDTETEGVPSTAIREISLLKELNHPNIVKLLDVI HTENKLYLVFEFLHQDLKKFMDASALTGIPLPLIKSYLFQLLQGLAFCHSHRVLHRDLKPQNLLINTEGA IKLADFGLARAFGVPVRTYTHEVVTLWYRAPEILLGCKYYSTAVDIWSLGCIFAEMVTRRALFPGDSEID QLFRIFRTLGTPDEVVWPGVTSMPDYKPSFPKWARQDFSKVVPPLDEDGRSLLSQMLHYDPNKRISAKAA LAHPFFQDVTKPVPHLRL An exemplary sequence of human Cyclin E1 is shown below: SEQ ID NO: 2 (UniProt Acession No. E1B9U2 ) 9 Attorney Docket No.49366-0051WO2 MPREKERDAKEPDTMKEESGTDVSVRSRKRKANVAVFLQDPDEEIAKIDRTVRSQCGSQPWDSN RACENPCSLIPTPDKEEDELLYPHAAYKPQRSTPSSSRASPLPVLNWANREEVWKIMLNKEKTY LRDKHLMQRHPLLQPKMRAILLDWLMEVCEVYKLHRETFYLAQDFFDRYMATQQNVVKTLLQLI GISSLFIAAKLEEIYPPKLHQFAYVTDGACSGDEILTMELIIMKALKWHLSPLTIVSWLNVYMQ VAYLNDVYEVLLPQYPQQIFIQIAELLDLCVLDVGCLEFSYGVLAASALYHFSSSELMQKVSGY QWCDIEKCVKWMVPFAIVIRETGSSKLKHFRGVPAEDAHNIQTHINSLDLLDKAQAKKAILSEE NRISPLPTGVLTPPQSSKKQSSGQGSA An exemplary sequence of human Cyclin E2 is shown below: SEQ ID NO: 3 (UniProt Accession No. O96020 ) MSRRSSRLQAKQQPQPSQTESPQEAQIIQAKKRKTTQDVKKRREEVTKKHQYEIRNCWPPVLSG GISPCIIIETPHKEIGTSDFSRFTNYRFKNLFINPSPLPDLSWGCSKEVWLNMLKKESRYVHDK HFEVLHSDLEPQMRSILLDWLLEVCEVYTLHRETFYLAQDFFDRFMLTQKDINKNMLQLIGITS LFIASKLEEIYAPKLQEFAYVTDGACSEEDILRMELIILKALKWELCPVTIISWLNLFLQVDAL KDAPKVLLPQYSQETFIQIAQLLDLCILAIDSLEFQYRILTAAALCHFTSIEVVKKASGLEWDS ISECVDWMVPFVNVVKSTSPVKLKTFKKIPMEDRHNIQTHTNYLAMLEEVNYINTFRKGGQLSP VCNGGIMTPPKSTEKPPGKH An exemplary sequence of human Cyclin A2 is shown below: SEQ ID NO: 4 (UniProt Accession No. P20248) MLGNSAPGPATREAGSALLALQQTALQEDQENINPEKAAPVQQPRTRAALAVLKSGNPRG LAQQQRPKTRRVAPLKDLPVNDEHVTVPPWKANSKQPAFTIHVDEAEKEAQKKPAESQKI EREDALAFNSAISLPGPRKPLVPLDYPMDGSFESPHTMDMSIILEDEKPVSVNEVPDYHE DIHTYLREMEVKCKPKVGYMKKQPDITNSMRAILVDWLVEVGEEYKLQNETLHLAVNYID RFLSSMSVLRGKLQLVGTAAMLLASKFEEIYPPEVAEFVYITDDTYTKKQVLRMEHLVLK VLTFDLAAPTVNQFLTQYFLHQQPANCKVESLAMFLGELSLIDADPYLKYLPSVIAGAAF HLALYTVTGQSWPESLIRKTGYTLESLKPCLMDLHQTYLKAPQHAQQSIREKYKNSKYHG VSLLNPPETLNL An exemplary sequence of human SKP2 is shown below: SEQ ID NO: 5 (UniProt Accession No. Q13309-1) MHRKHLQEIPDLSSNVATSFTWGWDSSKTSELLSGMGVSALEKEEPDSENIPQELLSNLGHPES PPRKRLKSKGSDKDFVIVRRPKLNRENFPGVSWDSLPDELLLGIFSCLCLPELLKVSGVCKRWY RLASDESLWQTLDLTGKNLHPDVTGRLLSQGVIAFRCPRSFMDQPLAEHFSPFRVQHMDLSNSV IEVSTLHGILSQCSKLQNLSLEGLRLSDPIVNTLAKNSNLVRLNLSGCSGFSEFALQTLLSSCS RLDELNLSWCFDFTEKHVQVAVAHVSETITQLNLSGYRKNLQKSDLSTLVRRCPNLVHLDLSDS VMLKNDCFQEFFQLNYLQHLSLSRCYDIIPETLLELGEIPTLKTLQVFGIVPDGTLQLLKEALP HLQINCSHFTTIARPTIGNKKNQEIWGIKCRLTLQKPSCL 10 Attorney Docket No.49366-0051WO2 CDK2 Inhibitors A “CDK2 inhibitor” as defined herein includes any compound exhibiting CDK2 inhibition activity. In some embodiments, a CDK2 inhibitor is selective for a CDK2 protein. Exemplary CDK2 inhibitors can exhibit inhibition activity (Ki) against CDK2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein or other similar assays to measure CDK2 inhibitory activity or designed to test similar activity and/or binding. In some embodiments, a CDK2 inhibitor can exhibit inhibition activity (Ki) against CDK2 of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay described herein or other similar assays to measure CDK2 inhibitory activity or designed to test similar activity and/or binding. In some embodiments, a CDK2 inhibitor exhibits a Ki against CDK2 of about 0.01 nM to about 5 nM, about 0.1 nM to about 10 nM, about 1 nM to about 50 nM, about 10 nM to about 100 nM, about 50 nM to about 250 nM, about 100 nM to about 500 nM, about 250 nM to about 750 nM, or about 500 nM to about 1,000 nM. Exemplary CDK2 inhibitors are described herein. A CDK2 inhibitor of Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: Ring A is absent, C6-C10 aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl; Ring B is absent, C3-C8 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; X is -NR^A-, -NHC(=O)-, -NHC(=O)CR^JR^K-, -NHC(=O)NH-, -NH(SO₂)-; Y is a bond or a C1-C6 alkylene; Z is absent, hydrogen, -C(=O)QC1-C6 alkyl, –Q(C=O)NR⁴R⁵, –Q(C=O)OC1-C6 alkyl, an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; 11 Attorney Docket No.49366-0051WO2 Q is a bond, -NR^A-, -O-, or CR^BR^C; each R¹ is independently (i) halogen, (ii) hydroxyl, (iii) cyano, (iv) C1-C6 haloalkyl optionally substituted with amino, (v) C1-C6 haloalkoxy, (vi) C1-C6 alkoxy optionally substituted with hydroxyl, (vii) C1-C8 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl, (viii) -(C1-C6 alkylene)_p-R⁶, (ix) 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, (x) C3-C6 cycloalkyl optionally substituted with amino, or (xi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or 4-8 membered heterocyclyl; R² is hydrogen, C1-C6 alkyl, or halogen; each R³ is independently halogen, hydroxyl, -NR^DR^E, C1-C6 haloalkyl, C1-C6 alkoxy, a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, or a C1-C6 alkyl optionally substituted with C6-C10 aryl or –C(=O)NR^FR^G; R⁴ and R⁵ are independently hydrogen, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, or C1-C6 alkyl optionally substituted with (i) C1-C6 alkoxy or (ii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; or R⁴ and R⁵, together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl and halogen; each R⁶ is independently (i) -C(=O)NR^DR^E, (ii) -NHC(=O)C1-C6 alkyl, (iii) -NR^FR^G, (iv) –S(=O)C1-C6 alkyl, (v) –(SO2)C1-C6 alkyl, (vi) –(SO₂)C3-C6 cycloalkyl, 12 Attorney Docket No.49366-0051WO2 (vii) –(C=O)C1-C6 alkyl, (viii) –(C=O)C3-C6 cycloalkyl, alkyl, 1-C6 alkyl, (xi) –(S(=NR^L)(=O))C1-C6 haloalkyl, (xii) –(S(=NR^L)(=O))C3-C6 cycloalkyl, (xiii) -(SO₂)NR^HR^I, or (xiv) –(SO₂)(5-6 membered heteroaryl optionally substituted with 1-2 independently selected C1-C6 alkyl each optionally substituted with hydroxyl); each R^A, R^B, R^C, R^D, R^E, R^F, R^G, R^J, and R^K are independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, 4-6 membered heterocyclyl, or C3-C8 cycloalkyl optionally substituted with –CO2H; or R^J and R^K, together with the carbon atom to which they are attached, form a C3-C5 cycloalkyl; each R^H and R^I are independently hydrogen, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl and C1-C6 haloalkyl; or R^H and R^I, together with the nitrogen to which they are attached, form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl and C1-C6 haloalkyl; R^L is hydrogen or C1-C6 alkyl optionally substituted with hydroxyl; m is 0, 1, 2, or 3; wherein when Ring A is absent m is 1; n is 0, 1, or 2; wherein when Ring B is absent, n is 0 or Z is absent; p is 0 or 1; wherein, when m is 1, n is 0, R¹ is dimethylamino, Ring B is cyclopentyl, X is -NH-, Y is a bond, Z is –Q(C=O)NR⁴R⁵, Q is O, R⁴ is hydrogen, and R⁵ is an unsubstituted C1-C6 alkyl; then Ring A is not a 9 membered heterocyclyl; and when m is 2, n is 0, one R¹ is an unsubstituted C1-C6 alkyl and the other R¹ is C1-C6 alkyl substituted with C1-C6 alkoxy, Ring A is a 5 membered heteroaryl, Ring B is cyclopentyl, Y is a 13 Attorney Docket No.49366-0051WO2 bond, Z is –Q(C=O)NR⁴R⁵, Q is O, R⁴ is hydrogen, and R⁵ is an unsubstituted C1-C6 alkyl; then X is not -NHC(=O)-. A CDK2 inhibitor of Formula (I-B), or a pharmaceutically acceptable salt thereof, wherein: R¹ is –NR^AR^B, –C(=O)NR^AR^B, –OC(=O)NR^AR^B, or an optionally substituted 5-10 membered heteroaryl; each R^A and R^B are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl; X is selected from the group consisting of: C2-C6 alkylene, , , , , , R² is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, or C3-C6 cycloalkoxy; R³ is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Y is –NR^C–, *–C(=O)NR^C(CR^DR^E)m–, *–NR^CC(=O)(CR^DR^E)m –, or –O–, wherein * indicates the point of connection to the pyrazole; 14 Attorney Docket No.49366-0051WO2 R^C is hydrogen or C1-C6 alkyl; m is 0, 1, or 2; each R^D and R^E are independently hydrogen, fluoro, or C1-C6 alkyl; and R⁴ is optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. A CDK2 inhibitor of Formula (I-C), or a pharmaceutically acceptable salt thereof, wherein: R¹ is –NR^AR^B, –C(=O)NR^AR^B, –OC(=O)NR^AR^B, an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each R^A and R^B are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl; X is –(CH2)aC3-C8 cycloalkylene-(CH2)b- optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; –(CH₂)_aC5-C8 cycloalkenylene-(CH2)b- optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; –(CH2)aphenylene-(CH2)b-; –(CH2)aheteroarylene-(CH2)b-; – (CH₂)_aheterocyclylene-(CH₂)_b-; and C2-C6 alkylene; a and b are independently 0, 1, or 2; X¹ is N or CR^X1; X² is N or CR^X2; R^X1 and R^X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1- C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Y is –NR^C–, *–C(=O)NR^C(CR^DR^E)n–, *–NR^CC(=O)(CR^DR^E)n –, or –O–, wherein * indicates the point of connection to the X¹-X² ring; R^C is hydrogen or C1-C6 alkyl; m is 0, 1, or 2; n is 0, 1, or 2; each R^D and R^E are independently hydrogen, fluoro, or C1-C6 alkyl; and 15 Attorney Docket No.49366-0051WO2 R² is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl. A CDK2 inhibitor of Formula (I-D), or a pharmaceutically acceptable salt thereof, wherein: Ring A is a C3-C10 cycloalkyl optionally substituted with 1-3 independently selected R¹; each R¹ is independently selected from halogen and C1-C6 alkyl; Ring B is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R²; each R² is independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl; Ring C is C4-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Ring C is optionally substituted with 1-3 independently selected R³; each R³ is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, C1-C6 haloalkoxy, -NR^AR^B, -SO₂R^A, -NHSO₂R^A, and –SO₂NR^AR^B; each R^A and R^B is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R^A and R^B together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; L¹ is a bond; L² is -NH- or –N(CH₃)-; L³ is a bond, -NH-, -N(CH3)-, -O-, *-SO2NH-, *-NHSO2-, *-C(=O)NH-, or *-NHC(=O)-, wherein * denotes the point of connection to Ring C; X is a C2-C15 alkylene, a C4-C15 alkenylene, or a C5-C15 alkynylene, wherein X is optionally substituted with 1-6 independently selected R^x and wherein 1-4 methylene units of X 16 Attorney Docket No.49366-0051WO2 are optionally and independently replaced by -O-, -NH-, -N(C1-C6 alkyl)-, -(C3-C6 cycloalkyl)-, or -(5-6 membered heteroaryl)-; each R^x is independently selected from halogen and C1-C6 alkyl; L⁴ is a bond, *-(CH₂)_m-O-C(=O)NH-, or *-(CH₂)_m-NHC(=O)NH-, wherein * indicates the point of attachment to Ring A; and m is 0, 1, or 2. Additional exemplary CDK2 inhibitors can be found in the following, each of which is incorporated by reference in their entireties: PCT Appl. Publication Nos. WO1999009030, WO1999015500, WO1999021845, WO1999061444, WO2000035908, WO2000035920, WO2000064900, WO2001014375, WO2001019825, WO2001072717, WO2002010141, WO2002018346, WO2002034721, WO2002044174, WO2002046182, WO2002059109, WO2002059111, WO2003002565, WO2003091246, WO2003097048, WO2003101989, WO2004004730, WO2004014864, WO2004014922, WO2004016597, WO2004016612, WO2004016613, WO2004018473, WO2004043467, WO2004043953, WO2004072063, WO2004078682, WO2004098520, WO2004108136, WO2005002552, WO2005005438, WO2005012256, WO2005012262, WO2005012298, WO2005026129, WO2005037843, WO2005042525, WO2005068468, WO2005075468, WO2005082903, WO2005116025, WO2006003440, WO2006008545, WO2006040049, WO2006050249, WO2006064251, WO2006070192, WO2006070195, WO2006070198, WO2006075152, WO2006077419, WO2006099974, WO2006105386, WO2006106046, WO2007015064, WO2007036732, WO2007042784, WO2007042786, WO2007060110, WO2007138268, WO2007138277, WO2007148070, WO2008045266, WO2008045267, WO2008045268, WO2008122767, WO2008130570, WO2008145678, WO2010100431, WO2012166463, WO2015124941, WO2017094026, WO2018033815, WO2019057825, WO2020157652, WO2020168197, WO2020180959, WO2020205560, WO2020206034, WO2020215156, WO2020223469, WO2020223558, WO2020239558, WO2021030537, WO2021072232, WO2021072475, WO2021170076, WO2021176349, WO2021236650, WO2022015670, WO2022051326, WO2022111621, WO2022111634, WO2022113003, WO2022135365, WO2022135442, WO2022140472, WO2022149057, WO2022155941, WO2022165513, WO2022166799, WO2022174031, WO2022179507, WO2022206888, WO2022236058, WO2022245776, WO2022266190, WO2022272106, WO2023239629, WO2022272106, WO2023034808, 17 Attorney Docket No.49366-0051WO2 WO2024026483, WO2024026481, WO2024026484, WO2024026486, WO2024039903, WO2023172921, WO2023168686, WO2024104455, WO2024039210, WO2024026479, WO2024039901, WO2023060057, WO2023274397, WO2023249974, WO2023092088, WO2023141852, WO2023278326, WO2023100134, WO2024102849, WO2023069700, WO2024092039, WO2023069720, WO2023023376, WO2024123801, WO2024059010, WO2023205892, WO2023240024, WO2023249968, WO2023249970, WO2023244710, WO2023250029, WO2024077216, WO2023192801, WO2023172957, WO2024066981, WO2023141571, WO2023056898, WO2023150612, WO2024086361, WO2024051727, WO2023160572, WO2023072096, WO2023059605, WO2023220640, WO2023059582, WO2023283315, WO2023154426, WO2023056069, WO2024127350, WO2023093769, WO2024046443, WO2024035830, WO2022225728, WO2023213271, WO2023226959, WO2023083201, WO2023051302, WO2023208143, WO2024171094, WO2021148793, WO2018138500, WO2008122767, WO2020157652, WO2023172921, WO2021072232, WO2024220731, WO2023249974, WO2023093769, WO2024127350, WO2025072462, WO2023192801, WO2022015670, WO2024102849, WO2023249968, WO2023250029, WO2023249970, WO2022140472, WO2023244710, WO2024243010, WO2024020380, WO2024020419, and WO2024092039. Additional exemplary CDK2 inhibitors include, but are not limited to, compounds in Table A. 18 Attorney Docket No.49366-0051WO2 Table A 19 Attorney Docket No.49366-0051WO2 (( m ( m ( m (( y (( y (( y 20 Attorney Docket No.49366-0051WO2 21 Attorney Docket No.49366-0051WO2 22 Attorney Docket No.49366-0051WO2 23 Attorney Docket No.49366-0051WO2 24 Attorney Docket No.49366-0051WO2 25 Attorney Docket No.49366-0051WO2 26 Attorney Docket No.49366-0051WO2 27 Attorney Docket No.49366-0051WO2 28 Attorney Docket No.49366-0051WO2 29 Attorney Docket No.49366-0051WO2 30 Attorney Docket No.49366-0051WO2 31 Attorney Docket No.49366-0051WO2 32 Attorney Docket No.49366-0051WO2 33 Attorney Docket No.49366-0051WO2 34 Attorney Docket No.49366-0051WO2 35 Attorney Docket No.49366-0051WO2 36 Attorney Docket No.49366-0051WO2 37 Attorney Docket No.49366-0051WO2 38 Attorney Docket No.49366-0051WO2 39 Attorney Docket No.49366-0051WO2 40 Attorney Docket No.49366-0051WO2 41 Attorney Docket No.49366-0051WO2 42 Attorney Docket No.49366-0051WO2 43 Attorney Docket No.49366-0051WO2 44 Attorney Docket No.49366-0051WO2 45 Attorney Docket No.49366-0051WO2 46 Attorney Docket No.49366-0051WO2 47 Attorney Docket No.49366-0051WO2 48 Attorney Docket No.49366-0051WO2 49 Attorney Docket No.49366-0051WO2 50 Attorney Docket No.49366-0051WO2 51 Attorney Docket No.49366-0051WO2 52 Attorney Docket No.49366-0051WO2 53 Attorney Docket No.49366-0051WO2 54 Attorney Docket No.49366-0051WO2 55 Attorney Docket No.49366-0051WO2 56 Attorney Docket No.49366-0051WO2 57 Attorney Docket No.49366-0051WO2 58 Attorney Docket No.49366-0051WO2 59 Attorney Docket No.49366-0051WO2 60 Attorney Docket No.49366-0051WO2 61 Attorney Docket No.49366-0051WO2 62 Attorney Docket No.49366-0051WO2 63 Attorney Docket No.49366-0051WO2 64 Attorney Docket No.49366-0051WO2 65 Attorney Docket No.49366-0051WO2 66 Attorney Docket No.49366-0051WO2 rac-3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazol- 3 l l l i idi 2 l i b lf id (1S*,3R*)-3-(2-((4-(N-(methyl- d₃)sulfamoyl)phenyl)amino)pyrimidin-5- yl)cyclopentyl ((S)-sec-butyl)carbamate 67 Attorney Docket No.49366-0051WO2 68 Attorney Docket No.49366-0051WO2 69 Attorney Docket No.49366-0051WO2 70 Attorney Docket No.49366-0051WO2 71 Attorney Docket No.49366-0051WO2 72 Attorney Docket No.49366-0051WO2 73 Attorney Docket No.49366-0051WO2 74 Attorney Docket No.49366-0051WO2 75 Attorney Docket No.49366-0051WO2 76 Attorney Docket No.49366-0051WO2 77 Attorney Docket No.49366-0051WO2 78 Attorney Docket No.49366-0051WO2 79 Attorney Docket No.49366-0051WO2 80 Attorney Docket No.49366-0051WO2 81 Attorney Docket No.49366-0051WO2 82 Attorney Docket No.49366-0051WO2 83 Attorney Docket No.49366-0051WO2 84 Attorney Docket No.49366-0051WO2 85 Attorney Docket No.49366-0051WO2 86 Attorney Docket No.49366-0051WO2 87 Attorney Docket No.49366-0051WO2 383 384 385 386 (3-(2-((2-fluoro-4-(N-(2-hydroxyethyl)sulfamoyl)phenyl)amino)pyrimidin-5- yl)cyclobutyl)methyl (S)-(4,4,4-trifluorobutan-2-yl)carbamate 387 oyl)phenyl)amino)pyrimidin-5- yl)cyclobutyl)methyl (S)-(4,4,4-trifluorobutan-2-yl)carbamate 388 3-(2-((4-(N-(2-hydroxyethyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl (S)-(444-trifluorobutan-2- l)carbamate 389 (1s,3R)-3-(2-((4-(N-(2-hydroxyethyl)sulfamoyl)phenyl)amino)pyrimidin-5- yl)cyclobutyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate 88 Attorney Docket No.49366-0051WO2 89 Attorney Docket No.49366-0051WO2 90 Attorney Docket No.49366-0051WO2 91 Attorney Docket No.49366-0051WO2 92 Attorney Docket No.49366-0051WO2 93 Attorney Docket No.49366-0051WO2 94 Attorney Docket No.49366-0051WO2 95 Attorney Docket No.49366-0051WO2 96 Attorney Docket No.49366-0051WO2 97 Attorney Docket No.49366-0051WO2 98 Attorney Docket No.49366-0051WO2 99 Attorney Docket No.49366-0051WO2 100 Attorney Docket No.49366-0051WO2 101 Attorney Docket No.49366-0051WO2 102 Attorney Docket No.49366-0051WO2 103 Attorney Docket No.49366-0051WO2 104 Attorney Docket No.49366-0051WO2 105 Attorney Docket No.49366-0051WO2 106 Attorney Docket No.49366-0051WO2 107 Attorney Docket No.49366-0051WO2 108 Attorney Docket No.49366-0051WO2 109 Attorney Docket No.49366-0051WO2 110 Attorney Docket No.49366-0051WO2 111 Attorney Docket No.49366-0051WO2 112 Attorney Docket No.49366-0051WO2 113 Attorney Docket No.49366-0051WO2 114 Attorney Docket No.49366-0051WO2 115 Attorney Docket No.49366-0051WO2 116 Attorney Docket No.49366-0051WO2 117 Attorney Docket No.49366-0051WO2 558 559 560 561 562 563 118 Attorney Docket No.49366-0051WO2 119 Attorney Docket No.49366-0051WO2 120 Attorney Docket No.49366-0051WO2 121 Attorney Docket No.49366-0051WO2 122 Attorney Docket No.49366-0051WO2 123 Attorney Docket No.49366-0051WO2 In some embodiments, a CDK2 inhibitor is selective for CDK2 over other cyclin dependent kinases, such as CDK1, CDK4, CDK6, CDK7, and/or CDK9, and/or selective for CDK2 over other kinases, such as GSK3, as measured in an assay described herein or other similar assays to 124 Attorney Docket No.49366-0051WO2 measure CDK2 inhibitory activity or designed to test similar activity and/or binding. A CDK2 inhibitor can be about 2-fold to about 10,000-fold, or more, selective for CDK2, for example, about 2-fold, about 10-fold, about 50-fold, about 100-fold, about 200 fold, about 300-fold, about 400- fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1,000- fold, about 1,500-fold, about 2,000-fold, about 2,500-fold, about 3,000-fold, about 3,500-fold, about 4,000-fold, about 4,500-fold, about 5,000-fold, about 5,500-fold, about 6,000-fold, about 6,500-fold, about 7,000-fold, about 7,500-fold, about 8,000-fold, about 8,500-fold, about 9,000- fold, about 9,500-fold, or about 10,000-fold selective for CDK2. In some embodiments, a CDK2 inhibitor is selective for CDK2 by about 2-fold to about 20-fold, about 5-fold to about 50-fold, about 10-fold to about 100-fold, about 20-fold to about 200-fold, about 50-fold to about 500-fold, about 100-fold to about 1,000 fold, about 200-fold to about 2,000-fold, about 300-fold to about 3,000-fold, about 400-fold to about 4,000 fold, about 500-fold to about 5,000-fold, about 600-fold to about 6,000-fold, about 700-fold to about 7,000 fold, about 800-fold to about 8,000-fold, about 900-fold to about 9,000-fold, or about 1,000-fold to about 10,000 fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK1 by about 2- fold, about 10-fold, about 50-fold, about 100-fold, about 200 fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1,000-fold, about 1,500-fold, about 2,000-fold, about 2,500-fold, about 3,000-fold, about 3,500-fold, about 4,000-fold, about 4,500-fold, about 5,000-fold, about 5,500-fold, about 6,000-fold, about 6,500- fold, about 7,000-fold, about 7,500-fold, about 8,000-fold, about 8,500-fold, about 9,000-fold, about 9,500-fold, or about 10,000-fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK1 by about 2-fold to about 20-fold, about 5-fold to about 50-fold, about 10-fold to about 100-fold, about 20-fold to about 200-fold, about 50-fold to about 500-fold, about 100- fold to about 1,000 fold, about 200-fold to about 2,000-fold, about 300-fold to about 3,000-fold, about 400-fold to about 4,000 fold, about 500-fold to about 5,000-fold, about 600-fold to about 6,000-fold, about 700-fold to about 7,000 fold, about 800-fold to about 8,000-fold, about 900-fold to about 9,000-fold, or about 1,000-fold to about 10,000 fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK4 by about 2- fold, about 10-fold, about 50-fold, about 100-fold, about 200 fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1,000-fold, about 1,500-fold, about 2,000-fold, about 2,500-fold, about 3,000-fold, about 3,500-fold, about 125 Attorney Docket No.49366-0051WO2 4,000-fold, about 4,500-fold, about 5,000-fold, about 5,500-fold, about 6,000-fold, about 6,500- fold, about 7,000-fold, about 7,500-fold, about 8,000-fold, about 8,500-fold, about 9,000-fold, about 9,500-fold, or about 10,000-fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK4 by about 2-fold to about 20-fold, about 5-fold to about 50-fold, about 10-fold to about 100-fold, about 20-fold to about 200-fold, about 50-fold to about 500-fold, about 100- fold to about 1,000 fold, about 200-fold to about 2,000-fold, about 300-fold to about 3,000-fold, about 400-fold to about 4,000 fold, about 500-fold to about 5,000-fold, about 600-fold to about 6,000-fold, about 700-fold to about 7,000 fold, about 800-fold to about 8,000-fold, about 900-fold to about 9,000-fold, or about 1,000-fold to about 10,000 fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK6 by about 2- fold, about 10-fold, about 50-fold, about 100-fold, about 200 fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1,000-fold, about 1,500-fold, about 2,000-fold, about 2,500-fold, about 3,000-fold, about 3,500-fold, about 4,000-fold, about 4,500-fold, about 5,000-fold, about 5,500-fold, about 6,000-fold, about 6,500- fold, about 7,000-fold, about 7,500-fold, about 8,000-fold, about 8,500-fold, about 9,000-fold, about 9,500-fold, or about 10,000-fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK6 by about 2-fold to about 20-fold, about 5-fold to about 50-fold, about 10-fold to about 100-fold, about 20-fold to about 200-fold, about 50-fold to about 500-fold, about 100- fold to about 1,000 fold, about 200-fold to about 2,000-fold, about 300-fold to about 3,000-fold, about 400-fold to about 4,000 fold, about 500-fold to about 5,000-fold, about 600-fold to about 6,000-fold, about 700-fold to about 7,000 fold, about 800-fold to about 8,000-fold, about 900-fold to about 9,000-fold, or about 1,000-fold to about 10,000 fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK7 by about 2- fold, about 10-fold, about 50-fold, about 100-fold, about 200 fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1,000-fold, about 1,500-fold, about 2,000-fold, about 2,500-fold, about 3,000-fold, about 3,500-fold, about 4,000-fold, about 4,500-fold, about 5,000-fold, about 5,500-fold, about 6,000-fold, about 6,500- fold, about 7,000-fold, about 7,500-fold, about 8,000-fold, about 8,500-fold, about 9,000-fold, about 9,500-fold, or about 10,000-fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK7 by about 2-fold to about 20-fold, about 5-fold to about 50-fold, about 10-fold to about 100-fold, about 20-fold to about 200-fold, about 50-fold to about 500-fold, about 100- 126 Attorney Docket No.49366-0051WO2 fold to about 1,000 fold, about 200-fold to about 2,000-fold, about 300-fold to about 3,000-fold, about 400-fold to about 4,000 fold, about 500-fold to about 5,000-fold, about 600-fold to about 6,000-fold, about 700-fold to about 7,000 fold, about 800-fold to about 8,000-fold, about 900-fold to about 9,000-fold, or about 1,000-fold to about 10,000 fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK9 by about 2- fold, about 10-fold, about 50-fold, about 100-fold, about 200 fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1,000-fold, about 1,500-fold, about 2,000-fold, about 2,500-fold, about 3,000-fold, about 3,500-fold, about 4,000-fold, about 4,500-fold, about 5,000-fold, about 5,500-fold, about 6,000-fold, about 6,500- fold, about 7,000-fold, about 7,500-fold, about 8,000-fold, about 8,500-fold, about 9,000-fold, about 9,500-fold, or about 10,000-fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK9 by about 2-fold to about 20-fold, about 5-fold to about 50-fold, about 10-fold to about 100-fold, about 20-fold to about 200-fold, about 50-fold to about 500-fold, about 100- fold to about 1,000 fold, about 200-fold to about 2,000-fold, about 300-fold to about 3,000-fold, about 400-fold to about 4,000 fold, about 500-fold to about 5,000-fold, about 600-fold to about 6,000-fold, about 700-fold to about 7,000 fold, about 800-fold to about 8,000-fold, about 900-fold to about 9,000-fold, or about 1,000-fold to about 10,000 fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK1, CDK4, CDK6, CDK7, and CDK9 by about 2-fold, about 10-fold, about 50-fold, about 100-fold, about 200 fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, about 1,000-fold, about 1,500-fold, about 2,000-fold, about 2,500-fold, about 3,000-fold, about 3,500-fold, about 4,000-fold, about 4,500-fold, about 5,000-fold, about 5,500- fold, about 6,000-fold, about 6,500-fold, about 7,000-fold, about 7,500-fold, about 8,000-fold, about 8,500-fold, about 9,000-fold, about 9,500-fold, or about 10,000-fold. In some embodiments, a CDK2 inhibitor is selective for CDK2 over CDK1, CDK4, CDK6, CDK7, and CDK9 by about 2-fold to about 20-fold, about 5-fold to about 50-fold, about 10-fold to about 100-fold, about 20- fold to about 200-fold, about 50-fold to about 500-fold, about 100-fold to about 1,000 fold, about 200-fold to about 2,000-fold, about 300-fold to about 3,000-fold, about 400-fold to about 4,000 fold, about 500-fold to about 5,000-fold, about 600-fold to about 6,000-fold, about 700-fold to about 7,000 fold, about 800-fold to about 8,000-fold, about 900-fold to about 9,000-fold, or about 1,000-fold to about 10,000 fold. 127 Attorney Docket No.49366-0051WO2 In some embodiments, a CDK2 inhibitor has inhibitory activity against CDK2, as described herein, but is selective for one or more of CDK1, CDK4, CDK6, CDK7, and CDK9 over CDK2 by about 1.1-fold to about 1,000-fold, for example, about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5- fold, about 9-fold, about 9.5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 150- fold, about 200-fold, about 250-fold, about 300-fold, about 350-fold, about 400-fold, about 450- fold, about 500-fold, about 550-fold, about 600-fold, about 650-fold, about 700-fold, about 750- fold, about 800-fold, about 850-fold, about 900-fold, about 950-fold, or about 1,000-fold. In some embodiments, a CDK2 inhibitor has inhibitory activity against CDK2, as described herein, but is selective for one or more of CDK1, CDK4, CDK6, CDK7, and CDK9 over CDK2 by about 1.1-fold to about 5-fold, about 1.5-fold to about 8 fold, about 2-fold to about 10-fold, about 5-fold to about 20-fold, about about 10-fold to about 50-fold, about 25-fold to about 75-fold, about 50-fold to about 100 fold, about 75-fold to about 200-fold, about 150-fold to about 300 fold, about 250-fold to about 500 fold, about 300-fold to about 600 fold, about 400-fold to about 700 fold, about 500-fold to about 800-fold, about 600-fold to about 900-fold, or about 700-fold to about 1,000-fold. In some embodiments, a CDK2 inhibitor has inhibitory activity against CDK2, as described herein, but is selective for CDK4 and/or CDK6 over CDK2 by about 1.1-fold to about 1,000-fold, for example, about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5- fold, about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 150-fold, about 200-fold, about 250-fold, about 300-fold, about 350-fold, about 400-fold, about 450-fold, about 500-fold, about 550-fold, about 600-fold, about 650-fold, about 700-fold, about 750-fold, about 800-fold, about 850-fold, about 900-fold, about 950-fold, or about 1,000-fold. In some embodiments, a CDK2 inhibitor has inhibitory activity against CDK2, as described 128 Attorney Docket No.49366-0051WO2 herein, but is selective for CDK4 and/or CDK6 over CDK2 by about 1.1-fold to about 5-fold, about 1.5-fold to about 8 fold, about 2-fold to about 10-fold, about 5-fold to about 20-fold, about about 10-fold to about 50-fold, about 25-fold to about 75-fold, about 50-fold to about 100 fold, about 75-fold to about 200-fold, about 150-fold to about 300 fold, about 250-fold to about 500 fold, about 300-fold to about 600 fold, about 400-fold to about 700 fold, about 500-fold to about 800- fold, about 600-fold to about 900-fold, or about 700-fold to about 1,000-fold. Methods of Treatment Some embodiments provide a method for treating a SKP2-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer is a SKP2-associated cancer. In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity, or level of any of the same, or any combination thereof (a SKP2-associated-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity, or level of any of the same, or any combination thereof (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity, or level of any of the same, or any combination thereof (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity, or level of any of the same, or any combination thereof (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a SKP2-associated-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity, or level 129 Attorney Docket No.49366-0051WO2 of any of the same, or any combination thereof. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity, or level of any of the same, or any combination thereof (a SKP2-associated-associated cancer). In some embodiments, a clinical trial protocol inclusion criteria indicates administration of a CDK2 inhibitor to a subject having a SKP2-associated cancer. In some embodiments, a package insert (e.g., a package insert approved by an appropriate regulartory agency) indicates administration of a CDK2 inhibitor to a subject having a SKP2-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor resistant to one or more previous therapies, for example, resistance to CDK4/CDK6 inhibition. In some embodiments, the subject has a cancer resistant to one or more previous therapies, for example, resistance to CDK4/CDK6 inhibition. In some embodiments, the subject has a tumor resistant to one or more previous therapies, for example, resistance to CDK4/CDK6 inhibition. In some embodiments, the subject has a tumor that is suspected of being resistant to one or more previous therapies, for example, resistance to CDK4/CDK6 inhibition. In some embodiments, the cancer (e.g., SKP2-associated cancer) is a solid tumor. In some embodiments, the cancer (e.g., SKP2-associated cancer) is colorectal cancer, lung cancer (including small cell lung carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), squamous cell carcinoma, and adenocarcinoma), head and neck squamous cell carcinoma (HNSCC), thyroid cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, or stomach (i.e., gastric) cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is selected from the group consisting of NSCLC, SCLC, bladder cancer, esophageal cancer, HNSCC, and gastric cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is NSCLC. In some embodiments, the cancer (e.g., SKP2-associated cancer) is SCLC. In some embodiments, the cancer (e.g., SKP2-associated cancer) is bladder cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is esophageal cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is HNSCC. 130 Attorney Docket No.49366-0051WO2 In some embodiments, the cancer (e.g., SKP2-associated cancer) is gastric cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is selected from the group consisting of breast cancer, ovarian cancer, and colorectal cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is colorectal cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is selected from the group consisting of breast cancer and ovarian cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is ovarian cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is breast cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is a breast cancer selected from the group consisting of: estrogen receptor (ER)-positive/hormone receptor (HR)-positive breast cancer, HER2-negative breast cancer; ER-positive/HR-positive breast cancer, HER2- positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer. In some embodiments, the cancer (e.g., SKP2-associated cancer) is a breast cancer selected from the group consisting of: endocrine resistant breast cancer, trastuzumab-resistant breast cancer, and breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the subject is a human. Some embodiments provide a method for treating a SKP2-associated cancer in a subject in need thereof, comprising: (a) identifying the cancer as being a SKP2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for treating a cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the subject has previously been identified or diagnosed as having a SKP2-associated cancer. Some embodiments provide a method of treating a SKP2-associated cancer, comprising 131 Attorney Docket No.49366-0051WO2 administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, to a subject previously identified or diagnosed as having a SKP2-associated cancer. Identifying the cancer identifying the cancer in the subject as a SKP2-associated cancer can be performed by any appropriate method. In some embodiments, the step of identifying the cancer in the subject as a SKP2-associated cancer includes performing an assay to detect dysregulation in a SKP2 gene, a SKP2 protein, or expression or activity or level of any of the same in a sample from the subject. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). An assay can be any appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). Some embodiments provide a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. Determining that the cancer is associated with a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity or level of any of the same (or any combination thereof), can be performed using any appropriate method. In some embodiments, the step of determining that the cancer in the subject is a SKP2-associated cancer includes performing an assay to detect dysregulation in a SKP2 gene, a SKP2 protein, or expression or activity or level of any of the same (or any combination thereof), in a sample from the subject. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). An assay can be any appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). Some embodiments provide a method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. 132 Attorney Docket No.49366-0051WO2 Some embodiments provide a method for inhibiting SKP2 activity in a mammalian cell, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. Some embodiments provide a method for inducing apoptosis in a mammalian cell, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. A mammalian cell can be any appropriate cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian SKP2-associated cancer cell. In some embodiments, the mammalian cell has dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity or level of any of the same (or any combination thereof). In some embodiments the CDK2 inhibitor is selected from Compounds 1-9, or a pharmaceutically acceptable salt thereof. Combinations In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and additional therapeutic agents such as those described herein. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or a pharmaceutically acceptable salt thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the 133 Attorney Docket No.49366-0051WO2 tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and undergo one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used after administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time after undergoing at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size (i.e. number of cells) of any remaining tumor after the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time after undergoing one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size (i.e. number of cells) of any remaining tumor after the one or more rounds of radiation therapy. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent), such as a kinase inhibitor (e.g., a CDK4/CDK6 inhibitor such as palbociclib, ribociclib, or abemaciclib), immunotherapy, and/or radiation. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is CDK2 inhibitor naïve. For example, the subject is naïve to treatment with a selective CDK2 inhibitor. In some embodiments, a subject is not CDK2 inhibitor naïve (i.e., the subject has been previously administered one or more CDK2 inhibitors). In some embodiments, a subject is CDK4/CDK6 inhibitor naïve. For example, the subject is naïve to treatment with a selective CDK4/CDK6 inhibitor. In some embodiments, a subject is not CDK4/CDK6 inhibitor naïve (i.e., the subject has been previously administered one or more CDK4/CDK6 inhibitors). In some embodiments of any of the methods described herein, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered in combination with a 134 Attorney Docket No.49366-0051WO2 therapeutically effective amount of at least one additional therapeutic agent. Non-limiting examples of additional therapeutic agents include: other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents such as EGFR, HER2, MEK, RAF, or KRAS inhibitors), cytotoxic chemotherapeutics, angiogenesis inhibitors, and radiotherapy. In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor typrosine kinase inhibitor (EGFR). For example, EGFR inhibitors can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa). In some embodiments, the additional therapeutic agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include trastuzumab and pertuzumab. In some embodiments, the additional therapeutic agent is an immunotherapy, for example, targeting PD-L1, CTLA-4, or PD-1. Exemplary immunotherapy agents include, but are not limited to pembrozolimab, ipilumimab, avelumab, nivolumab, and durvalumab. In some embodiments, the additional therapeutic agent is a Ras-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors, such as alpelisib, baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, regorafenib, ruxolitinib, tofacitinib, sorafenib, sunitinib, semaxanib, mobocertinib, avapritinib, fisogatinib, itacitinib, parsaclisib, pemigatinib, glesatinib, pexidartinib, rilzabrutinib, PF-477736 ((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H- pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide), PLX8394 ((3R)-N-[3-[5-(2- cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3- fluoropyrrolidine-1-sulfonamide), PRN1371 (8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6- dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one), TG101209 (N-t-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4- ylamino)benzenesulfonamide), NMS-1286937, NMS-088, INCB52793, PLX7486, PLX9486, and INCB40093. In some embodiments, the additional therapeutic agent is a cytotoxic chemotherapeutic. Non-limiting example of cytotoxic chemotherapeutics include bleomycin, bendamustine, fluorouracil, capecitabine, gemcitabine, vinorelbine, platinum agents such as carboplatin, 135 Attorney Docket No.49366-0051WO2 oxaliplatin, or cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, etoposide, irinotecan, lomustine, methotrexate, mitomycin C, abraxane, gemcitabine, palictaxel, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, mitoxantrone, teniposide, pemetrexed, taxanes such as cabazitaxel, paclitaxel, or docetaxel, temozolomide, vinblastine, and vincristine. In some embodiments, the additional therapeutic agent is a proteasome inhibitor, for example, bortezomib. In some embodiments, the additional therapeutic agent is a smoothened receptor antagonist, for example, vismodegib or sonidegib. In some embodiments, the additional therapeutic agent is an angiogenesis inhibitor, for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Examples of specific angiogenesis inhibitors include, but are not limited to, sunitinib (Sutent), bevacizumab (Avastin), axitinib, SU-14813, AG-13958, vatalanib (CGP79787), sorafenib (Nexavar), pegaptanib octasodium (Macugen), vandetanib (Zactima), PF-0337210, SU- 14843, AZD-2171, ranibizumab (Lucentis), Neovastat (AE941), tetrathiomolybdata (Coprexa), AMG706, VEGF Trap (AVE0005), CEP 7055, XL 880, telatinib, and CP-868,596. Other anti- angiogenesis agents include enzastaurin, midostaurin, perifosine, teprenone (Selbex) and UCN 01, lenalidomide (Revlimid), pomalidomide (Pomalyst), squalamine (Evizon), and thalidomide (Thalomid). In some embodiments, the additional therapeutic agent is an ALK, ROS, and/or TRK inhibitor, for example, larotrectinib, entrectinib, crizotinib, lorlatinib, In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, In some embodiments, the additional therapeutic agent is a BRAF inhibitor, for example, encorafinib, vemurafinib, dabrafenib, In some embodiments, the additional therapeutic agent is a PARP inhibitor, for example, olaparib, rucaparib, niraparib, or talazoparib. In some embodiments, the additional therapeutic agent is a Bcr-Abl inhibitor, for example, imatinib, dasatinib, or nilotinib. In some embodiments, the subject has a cancer that is known to be resistant to one of more 136 Attorney Docket No.49366-0051WO2 of the additional therapies described herein. Accordingly, some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the subject was previously administered one or more of a CDK4/CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), an endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), a HER2 inhibitor (such as neratinib, trastuzumab, dacomitinib, lapatinib, tucatinib, pertuzumab, or margetuximab), cytotoxic chemotherapeutic agents, an EGFR, MEK, RAF or KRAS inhibitor, an inhibitor of the Ras-Raf-MEK-ERK pathway, or a combination of any of the foregoing. In some embodiments, the subject was previously administered one or more of a CDK4/CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), an endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), a cytotoxic chemotherapeutic (as described herein), an EGFR, MEK, RAF or KRAS inhibitor (as described herein), an inhibitor of the Ras-Raf-MEK-ERK pathway (as described herein), or a combination of any of the foregoing, and the previous therapy was unsuccessful in treating the cancer. In some embodiments, the subject was previously administered a CDK4/CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), and the previous therapy was unsuccessful in treating the cancer. In some embodiments, the subject was previously administered a CDK4/CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib) as a monotherapy, and the previous therapy was unsuccessful in treating the cancer. Methods of Inhibiting Although the genetic basis of tumorigenesis may vary between different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During a metastatic cascade, the cancer cells lose growth inhibitory responses, undergo alterations in adhesiveness and produce enzymes that can degrade extracellular matrix components. This leads to detachment of tumor cells from the original tumor, infiltration into the circulation through newly formed vasculature, and/or migration and extravasation of the tumor cells at favorable distant sites where they may form colonies. Accordingly, also provided herein are methods for inhibiting metastasis of a cancer in a 137 Attorney Docket No.49366-0051WO2 subject having a cancer in need of such treatment (e.g., a subject at risk of developing metastasis), the method comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a SKP2-associated cancer. In some embodiments, the CDK2 inhibitor, or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent, as described herein. The term “metastasis” is an art known term and means the formation of an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject, where the additional tumor includes the same or similar cancer cells as the primary tumor. Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a SKP2-associated cancer that include: selecting, identifying, or diagnosing a subject as having a SKP2-associated cancer, and administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having a SKP2-associated cancer. Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a SK2-associated cancer that includes administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof to a subject having a SKP2-associated cancer. The decrease in the risk of developing a metastasis or an additional metastasis in a subject having a SKP2-associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the subject prior to treatment, or as compared to a subject or a population of subjects having a similar or the same SKP2-associated cancer that has received no treatment or a different treatment. The phrase “risk of developing a metastasis” means the risk that a subject having a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject over a set period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing a metastasis in a subject having a cancer are described herein. The phrase “risk of developing additional metastases” means the risk that a subject having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more further tumors distant from the primary tumor, where the further tumors 138 Attorney Docket No.49366-0051WO2 include the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastasis are described herein. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the cell. EXAMPLES Preparation of Compounds General methods for the preparation of selected compounds herein have been described in an illustrative manner and is intended to be description, rather than of limitation. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use provided herein, may be made without departing from the spirit and scope thereof. The synthesis of Compounds 1-593 is shown in PCT Publ. No. WO 2024/059010 A1. The synthesis of Compound 2 is shown in PCT Publ. No. WO2020157652 (see Example 13). The synthesis of Compound 3 is shown in PCT Publ. No. WO2018/033815 (see Example 10). The synthesis of Compound A is shown in, for example, U.S. Patent No.6,936,612. The synthesis of Compound B is shown in, for example, U.S. Patent No.7,855,211. Cell Culture-based Assays NCI-H2009, NCI-H650, and NCI-H1694 cell lines were obtained from ATCC. Cells were maintained in RPMI (Gibco 11875) media supplemented with 10% Fetal Bovine Serum, 1x Penicillin-Streptomycin at 37°C, 5% CO2. Data for selected assays are shown in Table 1. Phospho-Nucleolin T84 MSD Assay 139 Attorney Docket No.49366-0051WO2 NCI-H2009, NCI-H650, and NCI-H1694 cells were seeded at 15,000 cells per well in growth media in a 96-well tissue culture treated plate and allowed to adhere overnight at 37°C, 5% CO2. Next day, cells were treated with compound for 1hr at 37°C, 5% CO2. Cells were lysed and lysate was transferred to a pre-coated and blocked Anti-Nucleolin (Abcam, ab136649) MSD plate (MSD, L15XB-6) for an overnight incubation at 4°C. Plates were washed and phospho-Nucleolin T84 (Abcam, ab155977) detection antibody were added and incubated for 1.5 hrs at 37°C. After incubation, plates were washed and Anti-Rabbit Antibody (Goat) Sulfo-TAG Labeled (MSD, R32AB-5) was added and incubated for 30 minutes at 37°C. MSD GOLD Read Buffer B (MSD, R60AM-4) was used to develop signal and plates were read on the MSD plate reader after 10 minutes of incubation at RT. CyQUANT Anti-proliferation Assay NCI-H2009, NCI-H1694, and NCI-H650 cells were seeded at 2,000 cells per well in growth media in a 96-well tissue culture treated plate and allowed to adhere overnight at 37°C, 5% CO2. The next day, cells were treated with compound for 6 days (144hrs) at 37°C, 5% CO2. CyQUANT™ Direct Cell Proliferation Assay (Invitrogen C35011) was performed by following the manufacturer’s protocol. Plates were read on the Envision plate reader in fluorescence mode from bottom of the well at wavelengths (ex/em maxima 508/527 nm). The biological activity of selected compounds using the assays described above is shown in Table 1. Compound A is palbociclib, a CDK4/6 inhibitor included as a negative control. The Ki ranges are as follows: for CDK2/CCNA2 Ki (nM), A denotes < 0.1 nM; B denotes 0.1 nM ≤ Ki ≤ 1 nM; C denotes 1 nM ≤ Ki ≤ 10 nM; D denotes 10 nM ≤ Ki ≤ 100 nM; E denotes 100 nM ≤ Ki ≤ 500 nM; F denotes > 500 nM; and ND denotes “not determined.” For NCI-H1694 CyQuant Proliferation IC₅₀ (nM), A denotes < 50 nM; B denotes 50 nM ≤ Ki < 250 nM; C denotes 250 nM ≤ Ki ≤ 750 nM; D denotes > 750 nM; and ND denotes “not determined.” For NCI-H1694 pNCL T84 MSD IC₅₀ (nM), A denotes < 10 nM; B denotes 10 nM ≤ Ki < 100 nM; C denotes 100 nM ≤ Ki ≤ 1,000 nM; D denotes > 1,000 nM; and ND denotes “not determined.” 140 Attorney Docket No.49366-0051WO2 For NCI-H2009 pNCL T84 MSD IC₅₀ (nM), A denotes < 10 nM; B denotes 10 nM ≤ Ki < 100 nM; C denotes 100 nM ≤ Ki ≤ 1,000 nM; D denotes > 1,000 nM; and ND denotes “not determined.” For NCI-H2009 CyQuant Proliferation IC₅₀ (nM), A denotes < 10 nM; B denotes 10 nM ≤ Ki < 100 nM; C denotes 100 nM ≤ Ki ≤ 1,000 nM; D denotes > 1,000 nM; and ND denotes “not determined.” For NCI-H650 pNCL T84 MSD IC₅₀ (nM), A denotes < 10 nM; B denotes 10 nM ≤ Ki < 100 nM; C denotes 100 nM ≤ Ki ≤ 1,000 nM; D denotes > 1,000 nM; and ND denotes “not determined.” For NCI-H650 CyQuant Proliferation IC₅₀ (nM), A denotes < 10 nM; B denotes 10 nM ≤ Ki < 100 nM; C denotes 100 nM ≤ Ki ≤ 1,000 nM; D denotes > 1,000 nM; and ND denotes “not determined.” 141 Attorney Docket No.49366-0051WO2 Table 1: Selected Cell Culture Assay Data C M N N M N N M N N m S C C C C d ^I S C C p D-_H ^I-_H D^I- ^I S - D^I- ^I- . _{H H H H N} 65 65 16 16 2 2 o 0 0 9 9 00 0 . _{p C} 4 4 9 09 N y _pN _{C p}N _C C Q L u C yQ C yQ T ^a L u L u 8 _n 4 ^t _T ^a 8 _n t _T ^a 8 _n t 1 2 3 4 A 5 6 9 10 11 12 13 14 15 16 17 18 20 24 25 31 33 35 37 38 41 44 45 C C C 46 B B B 48 49 50 B C B 52 53 B C B 54 B C B 142 Attorney Docket No.49366-0051WO2 143 Attorney Docket No.49366-0051WO2 144 Attorney Docket No.49366-0051WO2 145 Attorney Docket No.49366-0051WO2 146 Attorney Docket No.49366-0051WO2 147 Attorney Docket No.49366-0051WO2 148 Attorney Docket No.49366-0051WO2 149 Attorney Docket No.49366-0051WO2 150 Attorney Docket No.49366-0051WO2 151 Attorney Docket No.49366-0051WO2 152 Attorney Docket No.49366-0051WO2 Stucture of Selected Compounds 153 Attorney Docket No.49366-0051WO2 154 Attorney Docket No.49366-0051WO2 155

Claims

Attorney Docket No.49366-0051WO2 WHAT IS CLAIMED IS: 1. A method for treating a SKP2-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 2. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer is a SKP2-associated cancer. 3. A method for treating a SKP2-associated cancer in a subject in need thereof, comprising: (a) identifying the cancer as being a SKP2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 4. A method for treating a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the cancer is a SKP2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 5. A method for treating a cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the subject has previously been identified or diagnosed as having a SKP2-associated cancer. 6. A method of treating a SKP2-associated cancer, comprising administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, to a subject previously identified or diagnosed as having a SKP2-associated cancer. 7. A method for treating cancer in a subject in need thereof, comprising: (a) determining or having determined that the cancer is associated with SKP2 amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 8. A method for treating cancer in a subject in need thereof, comprising: (a) determining or having determined that the subject has a dysregulation of a SKP2 gene, 156 Attorney Docket No.49366-0051WO2 a SKP2 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 9. A method for treating cancer in a subject in need thereof, comprising: (a) determining or having determined that the subject has a SKP2 amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 10. A method for treating cancer in a subject in need thereof, comprising: (a) determining or having determined that the subject exhibits overexpression of SKP2; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 11. A method for treating a SKP2-associated cancer in a subject in need thereof, comprising: (a) identifying the cancer as having a RICTOR amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 12. A method for treating a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the cancer has a RICTOR amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 13. A method for treating a cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the subject has previously been identified or diagnosed as having a RICTOR amplification. 14. A method of treating a SKP2-associated cancer, comprising administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, to a subject previously identified or diagnosed as (i) having a cancer and (ii) having a RICTOR amplification. 15. A method for treating cancer in a subject in need thereof, comprising: 157 Attorney Docket No.49366-0051WO2 (a) determining or having determined that the subject has a RICTOR amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 16. A method for inhibiting metastasis in a subject having a SKP2-associated cancer, comprising administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 17. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) identifying the cancer as being a SKP2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 18. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the cancer is a SKP2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 19. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the subject has previously been identified or diagnosed as having a SKP2-associated cancer. 20. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, to a subject previously identified or diagnosed as having a SKP2-associated cancer. 21. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the cancer is associated with SKP2 amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 158 Attorney Docket No.49366-0051WO2 22. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the subject has a dysregulation of a SKP2 gene, a SKP2 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 23. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the subject has a SKP2 amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 24. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the subject exhibits overexpression of SKP2; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 25. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) identifying the cancer as having a RICTOR amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 26. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the cancer has a RICTOR amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 27. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: 159 Attorney Docket No.49366-0051WO2 administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the subject has previously been identified or diagnosed as having a RICTOR amplification. 28. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, to a subject previously identified or diagnosed as (i) having a cancer and (ii) having a RICTOR amplification. 29. A method for inhibiting metastasis in a subject having a SKP2-associated cancer in a subject in need thereof, comprising: (a) determining or having determined that the subject has a RICTOR amplification; and (b) administering to the subject a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof. 30. A method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. 31. A method for inhibiting SKP2 activity in a mammalian cell, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. 32. A method for inducing apoptosis in a mammalian cell, comprising contacting the mammalian cell with a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; wherein the cell comprises a CDK2 protein and a SKP2 protein. 33. The method of any one of Claims 17-19, further comprising determining or having determined that the mammalian cell has a SKP2 amplification prior to contacting the mammalian cell with a CDK2 inhibitor. 34. The method of any one of Claims 17-19, further comprising determining or having determined that the mammalian cell has a RICTOR amplification prior to contacting the mammalian cell with a CDK2 inhibitor. 35. The method of any one of Claims 1-35, wherein the CDK2 inhibitor is selected from Compounds 1-593, or a pharmaceutically acceptable salt thereof. 160