Journal of Labelled Compounds and Radiopharmaceuticals, Aug 29, 2012
ABSTRACT 4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-ben... more ABSTRACT 4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid, PD0331179, was under investigation as a matrix metalloproteinase-13 inhibitor. 14 C-labeled and 2 H-labeled PD0331179 and its 2 H-labeled metabolite (PD0335699) were required to support its preclinical and clinical studies. [ 14 C] 3-phenyl-1-trimethyl/triphenylsilyl-propyne was efficiently prepared starting with [ 14 C] benzoic acid and used as a key-labeled reagent for the synthesis of [ 14 C] PD0331179. A one-pot coupling reaction between aryl iodide and trialkylsilyl propyne was developed to make this synthesis more efficient. The details of these syntheses are reported.
ABSTRACT Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical refer... more ABSTRACT Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical references (leaves 132-139). Microfilm. s
Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide on... more Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide oncogene that drives various cancers. Oncogenic RET induces abnormal activation of RET kinase, causing tumorigenesis. RET can be abnormally activated through RET point mutations and RET fusions. Although RET kinase has been discovered in tumors more than 30 years ago, patients with RET-altered tumors gain limited benefits from multikinase inhibitors (MKIs). In 2020, pralsetinib and selpercatinib were approved by FDA for the treatment of RET-altered tumors. Objective: Recently reported RET inhibitors were reviewed to provide an overview of the development of novel RET inhibitors. Methods: Literatures, patents, and conference proceedings published in the past five years were collected. Only RET inhibitors with novel scaffolds or in vivo efficacy were discussed in this review. The enzyme-based and cell-based activities, PK profiles, antitumor activities in vivo, and clinical efficacy of the selected RET inhibitors were described. Results: Great efforts have been spent on the development of RET inhibitors, leading to increased RET-targeted therapies. Due to high potency and specificity, pralsetinib and selpercatinib resulted in a >8-month improvement in overall survival, compared to MKIs. However, solvent-front mutants emerged and contributed to the acquired resistance to pralsetinib and selpercatinib. To overcome solvent front mutants, TPX-0046, TAS0953, and LOX-260 are investigated in early clinical studies. Conclusion: Zeteletinib, SYHA1815, TPX-0046, TAS0953, and LOX-260 are potential therapies for RET-altered cancers. In addition, macrocyclic inhibitors, allosteric inhibitors, and PROTACs are three promising strategies to address the potential drug resistance of RET.
Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical references (le... more Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical references (leaves 132-139). Microfilm. s
Journal of Labelled Compounds and Radiopharmaceuticals, Aug 29, 2012
ABSTRACT 4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-ben... more ABSTRACT 4-[1-Methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid, PD0331179, was under investigation as a matrix metalloproteinase-13 inhibitor. 14 C-labeled and 2 H-labeled PD0331179 and its 2 H-labeled metabolite (PD0335699) were required to support its preclinical and clinical studies. [ 14 C] 3-phenyl-1-trimethyl/triphenylsilyl-propyne was efficiently prepared starting with [ 14 C] benzoic acid and used as a key-labeled reagent for the synthesis of [ 14 C] PD0331179. A one-pot coupling reaction between aryl iodide and trialkylsilyl propyne was developed to make this synthesis more efficient. The details of these syntheses are reported.
ABSTRACT Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical refer... more ABSTRACT Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical references (leaves 132-139). Microfilm. s
Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide on... more Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide oncogene that drives various cancers. Oncogenic RET induces abnormal activation of RET kinase, causing tumorigenesis. RET can be abnormally activated through RET point mutations and RET fusions. Although RET kinase has been discovered in tumors more than 30 years ago, patients with RET-altered tumors gain limited benefits from multikinase inhibitors (MKIs). In 2020, pralsetinib and selpercatinib were approved by FDA for the treatment of RET-altered tumors. Objective: Recently reported RET inhibitors were reviewed to provide an overview of the development of novel RET inhibitors. Methods: Literatures, patents, and conference proceedings published in the past five years were collected. Only RET inhibitors with novel scaffolds or in vivo efficacy were discussed in this review. The enzyme-based and cell-based activities, PK profiles, antitumor activities in vivo, and clinical efficacy of the selected RET inhibitors were described. Results: Great efforts have been spent on the development of RET inhibitors, leading to increased RET-targeted therapies. Due to high potency and specificity, pralsetinib and selpercatinib resulted in a >8-month improvement in overall survival, compared to MKIs. However, solvent-front mutants emerged and contributed to the acquired resistance to pralsetinib and selpercatinib. To overcome solvent front mutants, TPX-0046, TAS0953, and LOX-260 are investigated in early clinical studies. Conclusion: Zeteletinib, SYHA1815, TPX-0046, TAS0953, and LOX-260 are potential therapies for RET-altered cancers. In addition, macrocyclic inhibitors, allosteric inhibitors, and PROTACs are three promising strategies to address the potential drug resistance of RET.
Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical references (le... more Typescript. Thesis (Ph. D.)--University of Montana, 1993. Includes bibliographical references (leaves 132-139). Microfilm. s
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