From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors

Nature Reviews Drug Discovery

Volumn 16, Issue 4, 2017, Pages 273-284

  Ashkenazi, Avi ^a   Fairbrother, Wayne J ^a   Leverson, Joel D ^b   Souers, Andrew J ^b  

^a GENENTECH INC   (United States)

^b ABBVIE INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; A 1155463; A 1331852; ANTINEOPLASTIC AGENT; AZD 4320; BCL 201; BH3 PROTEIN; BM 1197; NAVITOCLAX; PROTEIN BCL 2; PROTEIN BCL W; PROTEIN BCL X; PROTEIN BCL XL; PROTEIN INHIBITOR; S 44563; S 55746; UMI 77; UNCLASSIFIED DRUG; VENETOCLAX; WEHI 539;

APOPTOSIS; B CELL LYMPHOMA; CANCER THERAPY; CELL DEATH; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG DEVELOPMENT; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; HUMAN; NONHUMAN; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; ENZYMOLOGY; MOLECULARLY TARGETED THERAPY; NEOPLASMS; PATHOLOGY; PROCEDURES; PROTEIN DOMAIN;

ANTINEOPLASTIC AGENTS; APOPTOSIS; HUMANS; MOLECULAR STRUCTURE; MOLECULAR TARGETED THERAPY; NEOPLASMS; PROTEIN INTERACTION DOMAINS AND MOTIFS; PROTO-ONCOGENE PROTEINS C-BCL-2;

EID: 85013057082     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2016.253     Document Type: Review

References (107)

1. Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. B r. J. Cancer 26, 239-257 (1972).
2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
3. Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell 116, 205-219 (2004).
4. Ashkenazi, A. & Dixit, V. M. Death receptors: signaling and modulation. Science 281, 1305-1308 (1998).
5. Jin, Z. & El-Deiry, W. S. Overview of cell death signaling pathways. Cancer Biol. Ther. 4, 139-163 (2005).
6. Shamas-Din, A., Brahmbhatt, H., Leber, B. & Andrews, D. W. BH3-only proteins: orchestrators of apoptosis. Biochim. Biophys. Acta 1813, 508-520 (2011).
7. Chipuk, J. E., Moldoveanu, T., Llambi, F., Parsons, M. J. & Green, D. R. The BCL-2 family reunion. Mol. Cell 37, 299-310 (2010).
8. Czabotar, P. E., Lessene, G., Strasser, A. & Adams, J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49-63 (2014).
9. Tsujimoto, Y., Finger, L. R., Yunis, J., Nowell, P. C. & Croce, C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226, 1097-1099 (1984).
10. Tsujimoto, Y. et al. Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 224, 1403-1406 (1984).
11. Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440-442 (1988).
12. McDonnell, T. J. et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57, 79-88 (1989).
13. O'Neill, K. L., Huang, K., Zhang, J., Chen, Y. & Luo, X. Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane. Genes Dev. 30, 973-988 (2016).
14. Kang, M. H. & Reynolds, C. P. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 15, 1126-1132 (2009).
15. Amundson, S. A. et al. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60, 6101-6110 (2000).
16. Kitada, S., Pedersen, I. M., Schimmer, A. D. & Reed, J. C. Dysregulation of apoptosis genes in hematopoietic malignancies. Oncogene 21, 3459-3474 (2002).
17. Vaillant, F. et al. Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 24, 120-129 (2013).
18. Gandhi, L. et al. Phase I study of navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J. Clin. Oncol. 29, 909-916 (2011).
19. Bedikian, A. Y. et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J. Clin. Oncol. 24, 4738-4745 (2006).
20. Cao, X. X., Mohuiddin, I., Ece, F., McConkey, D. J. & Smythe, W. R. Histone deacetylase inhibitor downregulation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma. Am. J. Respir. Cell Mol. Biol. 25, 562-568 (2001).
21. Lessene, G., Czabotar, P. E. & Colman, P. M. BCL-2 family antagonists for cancer therapy. Nat. Rev. Drug Discov. 7, 989-1000 (2008).
22. L-Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983-986 (1997).
23. L-p53 interaction: insights from molecular dynamics simulations. PLoS ONE 6, e26014 (2011).
24. Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531-1534 (1996).
25. L. J. Med. Chem. 50, 641-662 (2007).
26. Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677-681 (2005).
27. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421-3428 (2008).
28. Shoemaker, A. R. et al. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin. Cancer Res. 14, 3268-3277 (2008).
29. Ackler, S. et al. The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemother. Pharmacol. 66, 869-880 (2010).
30. L/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivo. Mol. Cancer Ther. 10, 2340-2349 (2011).
31. Wilson, W. H. et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 11, 1149-1159 (2010).
32. Roberts, A. W. et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J. Clin. Oncol. 30, 488-496 (2012).
33. Kipps, T. J. et al. Navitoclax (ABT-263) plus fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR): a phase 1 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Blood 116, 2455 (2010).
34. Kipps, T. J. et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk. Lymphoma 56, 2826-2833 (2015).
35. Zhang, H. et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ. 14, 943-951 (2007).
36. Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173-1186 (2007).
37. Sleebs, B. E. et al. Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity. J. Med. Chem. 54, 1914-1926 (2011).
38. L inhibitor inducing complete and long-lasting tumor regression in vivo. PLoS ONE 9, e99404 (2014).
39. L induces antitumor activity in uveal melanoma patient-derived xenografts. PLoS ONE 9, e80836 (2014).
40. L inhibitor induces tumor cell apoptosis in a hematopoietic xenograft model. Blood 124, 5304 (2014).
41. Hennessy, E. J. et al. Discovery of potent inhibitors of the antiapoptotic proteins Bcl-2 and Bcl-xL, resulting in the identification of a clinical candidate for the treatment of cancer (AZD4320). ACS Medicinal Chemistry annual meeting https://www.acsmedchem. org/ama/orig/abstracts/mediabstractf2015.pdf abstr. 24 (2015).
42. Huang, J. Z. et al. The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood 99, 2285-2290 (2002).
43. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202-208 (2013).
44. Ackler, S. et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol. Res. Perspect. 3, e00178 (2015).
45. Roberts, A. W. et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 311-322 (2016).
46. Stilgenbauer, S. et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 17, 768-778 (2016).
47. Jones, J. A. et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to ibrutinib or idelalisib therapy. Blood 126, 715 (2015).
48. Ma, S. et al. Deep and durable responses following venetoclax (ABT-199/GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1b study. Blood 126, 830 (2015).
49. Flinn, I. W. et al. Safety and efficacy of a combination of venetoclax (GDC-0199/ABT-199) and obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia: results from an ongoing phase 1b study (GP28331). Blood 126, 494 (2015).
50. Salles, G. et al. Updated safety and preliminary efficacy data from a phase 1b study combining venetoclax (GDC0199, ABT199) with bendamustine/rituximab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia. Blood 126, 829 (2015).
51. Gerecitano, J. F. et al. A phase 1 study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with relapsed/refractory non-Hodgkin lymphoma. Blood 126, 254 (2015).
52. de Vos, S. et al. A dose-escalation study of venetoclax (ABT-199/GDC-0199) in combination with bendamustine and rituximab in patients with relapsed or refractory non-Hodgkin's lymphoma. Blood 126, 255 (2015).
53. Konopleva, M. et al. A phase 2 study of ABT-199 (GDC-0199) in patients with acute myelogenous leukemia (AML). Blood 124, 118 (2014).
54. DiNardo, C. et al. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are ≥65 years and not eligible for standard induction therapy. Blood 126, 327 (2015).
55. Kumar, S. et al. Safety and efficacy of venetoclax (ABT-199/GDC-0199) monotherapy for relapsed/refractory multiple myeloma: phase 1 preliminary results. Blood 126, 4219 (2015).
56. Moreau, P. et al. Safety and efficacy of venetoclax (ABT-199/GDC-0199) in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma: phase 1b results. Blood 126, 3038 (2015).
57. Seymour, J. F. et al. Reduction of tumor lysis syndrome (TLS) risk in chronic lymphocytic leukemia (CLL) patients treated with ABT-199 (GDC-0199): results of modifications to dosing schedule and TLS prophylaxis [abstract P868]. Haematologica 99 (Suppl. 1), 321 (2014).
58. Casara, P. et al. Novel derivatives of indole and pyrrole, method for the production thereof and pharmaceutical compositions containing same. World Intellectual Property Organization patent WO2015011396 (2015).
59. Porter, J. et al. Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selective Bcl-2 inhibitors. Bioorg. Med. Chem. Lett. 19, 230-233 (2009).
60. International Standard Randomised Controlled Trial Number Registry. ISRCTN http://www.isrctn.com/ISRCTN04804337 (2016).
61. Garcia, M. et al. Phase 1 trial with Bcl-2 inhibitor S55746 in t(11:14) multiple myeloma. Health Research Authority http://www.hra.nhs.uk/news/research-summaries/phase-1-trial-with-bcl-2-inhibitor-s55746-in-t1114-multiple-myeloma/(2016)
62. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02603445 (2016).
63. L can confer a multidrug resistance phenotype. Blood 86, 1903-1910 (1995).
64. Leverson, J. D. et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci. Transl Med. 7, 279ra240 (2015).
65. L inhibitor. Nat. Chem. Biol. 9, 390-397 (2013).
66. L inhibitor with in vivo activity. ACS Med. Chem. Lett. 5, 1088-1093 (2014).
67. L. ACS Med. Chem. Lett. 5, 662-667 (2014).
68. Koss, B. et al. Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines. Oncotarget 7, 11500-11511 (2016).
69. Lopez, J. et al. Mito-priming as a method to engineer Bcl-2 addiction. Nat. Commun. 7, 10538 (2016).
70. Puglisi, M. et al. A phase I safety and pharmacokinetic (PK) study of navitoclax (N) in combination with docetaxel (D) in patients (pts) with solid tumors. J. Clin. Oncol. 29, 2518 (2011).
71. L as a critical survival factor in a subset of colorectal cancer. Mol. Cancer 14, 126 (2015).
72. Perciavalle, R. M. & Opferman, J. T. Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol. 23, 22-29 (2013).
73. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899-905 (2010).
74. L is an essential survival protein of human myeloma cells. Blood 100, 194-199 (2002).
75. Zhang, B., Gojo, I. & Fenton, R. G. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood 99, 1885-1893 (2002).
76. Glaser, S. P. et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 26, 120-125 (2012).
77. Song, L., Coppola, D., Livingston, S., Cress, D. & Haura, E. B. Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. Cancer Biol. Ther. 4, 267-276 (2005).
78. Zhang, H. et al. Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines. Oncogene 30, 1963-1968 (2011).
79. Kelly, G. L. et al. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev. 28, 58-70 (2014).
80. Bose, P. & Grant, S. Mcl-1 as a therapeutic target in acute myelogenous leukemia (AML). Leuk. Res. Rep. 2, 12-14 (2013).
81. Konopleva, M. et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375-388 (2006).
82. van Delft, M. F. et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389-399 (2006).
83. Tahir, S. K. et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 67, 1176-1183 (2007).
84. Wei, S. H. et al. Inducing apoptosis and enhancing chemosensitivity to gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell. Cancer Chemother. Pharmacol. 62, 1055-1064 (2008).
85. Wertz, I. E. et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471, 110-114 (2011).
86. Akagi, H. et al. Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells. Gastric Cancer 16, 100-110 (2013).
87. Lee, E. F. et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J. Cell Biol. 180, 341-355 (2008).
88. Lee, E. F. et al. Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands. J. Biol. Chem. 284, 30508-30517 (2009).
89. Stewart, M. L., Fire, E., Keating, A. E. & Walensky, L. D. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat. Chem. Biol. 6, 595-601 (2010).
90. Muppidi, A. et al. Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors. J. Am. Chem. Soc. 134, 14734-14737 (2012).
91. Smith, B. J. et al. Structure-guided rational design of a/p-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. Chembiochem 14, 1564-1572 (2013).
92. Belmar, J. & Fesik, S. W. Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol. Ther. 145, 76-84 (2015).
93. Varadarajan, S. et al. Evaluation and critical assessment of putative MCL-1 inhibitors. Cell Death Differ. 20, 1475-1484 (2013).
94. Abulwerdi, F. et al. A novel small-molecule inhibitor of Mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol. Cancer Ther. 13, 565-575 (2014).
95. Richard, D. J. et al. Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker. Bioorg. Med Chem. 21, 6642-6649 (2013).
96. Elmore, S. W. et al. 7-substituted indole MCL-1 inhibitors. World Intellectual Property Organization patent WO2008131000 A2 (2008).
97. Leverson, J. D. et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 6, e1590 (2015).
98. Bruncko, M. et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J. Med. Chem. 58, 2180-2194 (2015).
99. Burke, J. P. et al. Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design. J. Med. Chem. 58, 3794-3805 (2015).
100. Pelz, N. F. et al. Discovery of 2-indole-acylsulfonamide myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods. J. Med. Chem. 59, 2054-2066 (2016).
101. Sensintaffar, J. L. et al. Small molecule Mcl-1 inhibitors induce apoptosis and death in multiple cancer subtypes in vitro. Cancer Res. 76 (14 Suppl.), abstr. 3727 (2016).
102. Kotschy, A. New thienopyrimidine derivatives, a process for their preparation and pharmaceutical compositions containing them. European patent EP2886545 B1 (2016).
103. Kotschy, A. et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538, 477-482 (2016).
104. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02675452 (2016).
105. AbbVie. Venetoclax receives 3rd breakthrough therapy designation from the FDA for the combination treatment of patients with untreated acute myeloid leukemia not eligible for standard induction chemotherapy. PR Newswire http://wwwprnewswire. com/news-releases/venetoclax-receives-3rd-breakthrough-therapy-designation-from-the-fda-for-the-combination-treatment-of-patients-with-untreated-acute-myeloid-leukemia-not-eligible-for-standard-induction-chemotherapy-300211208.html (2016).
106. L revealed by crystal structure and comparative analysis. Proteins 83, 1262-1272 (2015).
107. Brown, S. P. et al. Tetrahydronapthalene derivatives that inhibit MCL-1 protein. World Intellectual Property Organization patent WO2016033486 (2016).