Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer
"> Figure 1
<p>Expression of Bcl-2 in cancer. Bar charts showing the expression in different tumor histotypes of Bcl-2 mRNA, reported as fragments per kilobase of exon model per million reads mapped (FPKM), and protein, detected by immunohistochemistry and reported as percentages of positive patient samples. Data are from The Human Protein Atlas database (<a href="https://www.proteinatlas.org/" target="_blank">https://www.proteinatlas.org/</a>).</p> "> Figure 2
<p>Expression of Bcl-xL in cancer. Bar charts showing the expression in different tumor histotypes of Bcl-xL mRNA, reported as fragments per kilobase of exon model per million reads mapped (FPKM), and protein, detected by immunohistochemistry and reported as percentages of positive patient samples. Data are from The Human Protein Atlas database (<a href="https://www.proteinatlas.org/" target="_blank">https://www.proteinatlas.org/</a>).</p> "> Figure 3
<p>Expression of Mcl-1 in cancer. Bar charts showing the expression in different tumor histotypes of Mcl-1 mRNA, reported as fragments per kilobase of exon model per million reads mapped (FPKM), and protein, detected by immunohistochemistry and reported as percentages of positive patient samples. Data are from The Human Protein Atlas database (<a href="https://www.proteinatlas.org/" target="_blank">https://www.proteinatlas.org/</a>).</p> "> Figure 4
<p>Bubble chart showing the number of published papers in the last 30 years regarding Bcl-2, Bcl-xL, Mcl-1, Bcl-w, Bcl-B and A1/Bfl-1 anti-apoptotic proteins associated with apoptosis, cancer, therapy or resistance.</p> "> Figure 5
<p>Schematic representation of BH3 mimetics. For each BH3 mimetic the corresponding Bcl-2 anti-apoptotic protein targets are indicated by lines categorizing BH3 mimetics according to their specificity (multitargets, dual or specific inhibitors). * Sabutoclax is not reported to inhibit Bcl-w.</p> ">
Abstract
:1. Introduction
2. Relevance of Bcl-2 Anti-Apoptotic Family Proteins in Cancer
2.1. Bcl-2
2.2. Bcl-xL (BCL2-like 1 Gene, BCL2L1)
2.3. Mcl-1 (Myeloid Leukemia Sequence 1)
3. Anti-Apoptotic Bcl-2 Family Protein Inhibitors
3.1. Antisense Oligonucleotides
3.2. BH3 Mimetics
3.2.1. Rationale for the Use of BH3 Mimetics (Priming and Protein Addiction)
3.2.2. Multitarget BH3 Mimetics
3.2.3. Dual BH3 Inhibitors: Bcl-2/Bcl-xL, Bcl-2/Mcl-1, Bcl-xL/Mcl-1
3.2.4. Bcl-2 Specific Inhibition
3.2.5. Bcl-xL Specific Inhibition
3.2.6. Mcl-1 Specific Inhibition
3.3. BH3 Peptides
3.4. Molecules Promoting Protein Conformational Change
3.5. Bcl-2 Quadruplex Selective Approach
4. Vaccination Using Anti-Apoptotic Protein-Derived Peptides
5. Pro-Apoptotic Bcl-2 Family Protein Activations
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Inhibitor | Specificity | Clinical Trial Identifier | Tumor Histotype | Phase | Combination with |
---|---|---|---|---|---|
Navitoclax | Bcl-2/Bcl-xL/ Bcl-w | NCT04041050 | myelo- proliferative neoplasm | I | Ruxolitinib or single agent |
NCT03222609 | myelofibrosis | II | Ruxolitinib or single agent | ||
NCT00788684 | lymphoid cancers | I | Ruxolitinib | ||
NCT02520778 | advanced or metastatic non-small lung cancer | I | Osimertinib | ||
NCT02143401 | relapsed or refractory solid tumors | I | Sorafenib | ||
NCT02079740 | advanced or metastatic solid tumors | I/II | Trametinib | ||
NCT01989585 | BRAF mutant melanoma | I/II | Dabrafenib/ Trametinib | ||
APG-1252 | Bcl-2/Bcl-xL | NCT03080311 | small cell lung cancer or other solid tumors | I | single agent |
NCT04210037 | relapsed/ refractory small cell lung cancer | I/II | Paclitaxel | ||
AZD0466 | Bcl-2/Bcl-xL | NCT04214093 | hematologic or solid tumors | I | single agent |
Venetoclax | Bcl-2 | NCT03000257 | advanced solid tumors | I | ABBV-181 |
NCT03082209 | previously treated solid tumors and hematologic malignancies | I | ABBV-621 | ||
NCT03181126 | relapsed/ refractory acute lymphoblastic leukemia and relapsed/ refractory lymphoblastic lymphoma | I | Navitoclax | ||
NCT04029688 | relapsed/refractory acute leukemias or solid tumors | I/II | Idasanutlin | ||
S65487 | Bcl-2 | NCT03755154 | acute myeloid leukemia, non-Hodgkin lymphoma or multiple myeloma | I | single agent |
AMG-176 | Mcl-1 | NCT02675452 | relapsed or refractory multiple myeloma and subjects with relapsed or refractory acute myeloid leukemia | I | single agent |
AZD5991 | Mcl-1 | NCT03218683 | relapsed or refractory hematologic malignancies | II | Venetoclax |
S64315/ MIK665 | Mcl-1 | NCT02979366 | acute myeloid leukemia or myelodysplastic syndrome | I | single agent |
NCT02992483 | refractory or relapsed lymphoma or multiple myeloma | I | single agent | ||
NCT03672695 | acute myeloid leukemia | I | Venetoclax |
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D’Aguanno, S.; Del Bufalo, D. Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer. Cells 2020, 9, 1287. https://doi.org/10.3390/cells9051287
D’Aguanno S, Del Bufalo D. Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer. Cells. 2020; 9(5):1287. https://doi.org/10.3390/cells9051287
Chicago/Turabian StyleD’Aguanno, Simona, and Donatella Del Bufalo. 2020. "Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer" Cells 9, no. 5: 1287. https://doi.org/10.3390/cells9051287