BCL-2: Long and winding path from discovery to therapeutic target

Biochemical and Biophysical Research Communications

Volumn 482, Issue 3, 2017, Pages 459-469

  Schenk, Robyn L ^a,b   Strasser, Andreas ^a,b   Dewson, Grant ^a,b  

^a WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

ABT 199; Apoptosis; BCL 2; BH3 Mimetics; Cancer; Venetoclax

Indexed keywords

ANTINEOPLASTIC AGENT; NAVITOCLAX; PROTEIN BCL 2; PROTEIN INHIBITOR; VENETOCLAX; ANILINE DERIVATIVE; FUSED HETEROCYCLIC RINGS; SULFONAMIDE;

APOPTOSIS; CANCER GROWTH; DRUG DESIGN; DRUG SCREENING; DRUG TARGETING; HUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; NEOPLASMS; PHYSIOLOGY; PROTEIN PROTEIN INTERACTION; PROTO ONCOGENE;

ANILINE COMPOUNDS; ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BRIDGED BICYCLO COMPOUNDS, HETEROCYCLIC; DRUG DESIGN; DRUG DISCOVERY; GENES, BCL-2; HUMANS; NEOPLASMS; PROTEIN INTERACTION MAPS; PROTO-ONCOGENE PROTEINS C-BCL-2; SULFONAMIDES;

EID: 85012886240     PISSN: 0006291X     EISSN: 10902104     Source Type: Journal    
DOI: 10.1016/j.bbrc.2016.10.100     Document Type: Review

References (158)

1. [1] Kerr, J.F.R., Wyllie, A.H., Currie, A.R., Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26 (1972), 239–257.
2. [2] Youle, R.J., Strasser, A., The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell. Biol. 9 (2008), 47–59.
3. [3] 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 (2014), 49–63.
4. [4] Leber, B., Lin, J., Andrews, D.W., Still embedded together binding to membranes regulates Bcl-2 protein interactions. Oncogene 29 (2010), 5221–5230.
5. [5] Llambi, F., Green, D.R., Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr. Opin. Genet. Dev. 21 (2011), 12–20.
6. [6] Hanahan, D., Weinberg, R.A., The hallmarks of cancer. Cell 100 (2000), 57–70.
7. [7] Czabotar, P.E., Lessene, G., Bcl-2 family proteins as therapeutic targets. Curr. Pharm. Des. 16 (2010), 3132–3148.
8. [8] Sarosiek, K.A., Letai, A., Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics - recent successes, current challenges and future promise. FEBS J. 283 (2016), 3523–3533.
9. [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 (1984), 1097–1099.
10. [10] Fukuhara, S., Rowley, J.D., Variakojis, D., Golomb, H.M., Chromosome abnormalities in poorly differentiated lymphocytic lymphoma. Cancer Res. 39 (1979), 3119–3128.
11. [11] Manolov, G., Manolova, Y., Marker band in one chromosome 14 from Burkitt lymphomas. Nature 237 (1972), 33–34.
12. [12] Yunis, J.J., Oken, M.M., Kaplan, M.E., Ensrud, K.M., Howe, R.R., Theologides, A., Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin's lymphoma. N. Engl. J. Med. 307 (1982), 1231–1236.
13. [13] Levine, P.H., Connelly, R.R., McKay, F.W., Burkitt's lymphoma in the USA: cases reported to the American Burkitt Lymphoma Registry compared with population-based incidence and mortality data. IARC Sci. Publ., 1985, 217–224.
14. H on chromosome 14 and near a transcriptional unit on 18. Cell 41 (1985), 899–906.
15. [15] Cleary, M.L., Sklar, J., Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc. Natl. Acad. Sci. U. S. A. 82 (1985), 7439–7443.
16. [16] Graninger, W.B., Seto, M., Boutain, B., Goldman, P., Korsmeyer, S.J., Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. J. Clin. Invest. 80 (1987), 1512–1515.
17. [17] Seto, M., Jaeger, U., Hockett, R.D., Graninger, W., Bennett, S., Goldman, P., Korsmeyer, S.J., Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. EMBO J. 7 (1988), 123–131.
18. [18] Cleary, M.L., Smith, S.D., Sklar, J., Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47 (1986), 19–28.
19. [19] Tsujimoto, Y., Croce, C.M., Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl. Acad. Sci. U. S. A. 83 (1986), 5214–5218.
20. [20] Tsujimoto, Y., Ikegaki, N., Croce, C.M., Characterization of the protein product of bcl-2, the gene involved in human follicular lymphoma. Oncogene 2 (1987), 3–7.
21. [21] Tsujimoto, Y., Gorham, J., Cossman, J., Jaffe, E., Croce, C.M., The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229 (1985), 1390–1393.
22. [22] Bakhshi, A., Wright, J.J., Graninger, W., Seto, M., Owens, J., Cossman, J., Jensen, J.P., Goldman, P., Korsmeyer, S.J., Mechanism of the t(14;18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners. Proc. Natl. Acad. Sci. U. S. A. 84 (1987), 2396–2400.
23. [23] Reed, J.C., Tsujimoto, Y., Alpers, J.D., Croce, C.M., Nowell, P.C., Regulation of bcl-2 proto-oncogene expression during normal human lymphocyte proliferation. Science 236 (1987), 1295–1299.
24. [24] Negrini, M., Silini, E., Kozak, C., Tsujimoto, Y., Croce, C.M., Molecular analysis of mbcl-2: structure and expression of the murine gene homologous to the human gene involved in follicular lymphoma. Cell 49 (1987), 455–463.
25. [25] Gurfinkel, N., Unger, T., Givol, D., Mushinski, J.F., Expression of the bcl-2 gene in mouse B lymphocytic cell lines is differentiation stage specific. Eur. J. Immunol. 17 (1987), 567–570.
26. [26] Reed, J.C., Cuddy, M., Slabiak, T., Croce, C.M., Nowell, P.C., Oncogenic potential of bcl-2 demonstrated by gene transfer. Nature 336 (1988), 259–261.
27. [27] 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 (1988), 440–442.
28. [28] Tsujimoto, Y., Stress-resistance conferred by high level of bcl-2 alpha protein in human B lymphoblastoid cell. Oncogene 4 (1989), 1331–1336.
29. [29] Strasser, A., Harris, A.W., Cory, S., Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67 (1991), 889–899.
30. [30] Nuñez, G., London, L., Hockenbery, D., Alexander, M., McKearn, J.P., Korsmeyer, S.J., Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J. Immunol. 144 (1990), 3602–3610.
31. [31] Strasser, A., Harris, A.W., Vaux, D.L., Webb, E., Bath, M.L., Adams, J.M., Cory, S., Abnormalities of the immune system induced by dysregulated bcl-2 expression in transgenic mice. Curr. Top. Microbiol. Immunol. 166 (1990), 175–181.
32. [32] Strasser, A., Whittingham, S., Vaux, D.L., Bath, M.L., Adams, J.M., Cory, S., Harris, A.W., Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. U. S. A. 88 (1991), 8661–8665.
33. [33] McDonnell, T.J., Deane, N., Platt, F.M., Nuñez, G., Jaeger, U., McKearn, J.P., Korsmeyer, S.J., bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57 (1989), 79–88.
34. [34] Sentman, C.L., Shutter, J.R., Hockenbery, D., Kanagawa, O., Korsmeyer, S.J., bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67 (1991), 879–888.
35. [35] Nuñez, G., Seto, M., Seremitis, S., Ferrero, D., Grignani, F., Korsmeyer, S.J., Dalla-Favera, R., Growth- and tumor-promoting effects of deregulated BCL2 in human B-lymphoblastoid cells. Proc. Natl. Acad. Sci. U. S. A. 86 (1989), 4589–4593.
36. [36] McDonnell, T.J., Nuñez, G., Platt, F.M., Hockenbery, D., London, L., McKearn, J.P., Korsmeyer, S.J., Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population. Mol. Cell. Biol. 10 (1990), 1901–1907.
37. [37] McDonnell, T.J., Korsmeyer, S.J., Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349 (1991), 254–256.
38. [38] Strasser, A., Harris, A.W., Cory, S., The bcl-2 oncogene regulates lymphocyte survival and potentiates lymphomagenesis. Watters, M.L.A.D., (eds.) Cell Death: the Cellular and Molecular Basis of Apoptosis, 1993, Harwood Academic Publishers, 167–177.
39. [39] Ogilvy, S., Metcalf, D., Print, C.G., Bath, M.L., Harris, A.W., Adams, J.M., Constitutive bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc. Natl. Acad. Sci. U. S. A. 96 (1999), 14943–14948.
40. [40] Egle, A., Harris, A.W., Bath, M.L., O'Reilly, L., Cory, S., VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103 (2004), 2276–2283.
41. [41] Strasser, A., Harris, A.W., Bath, M.L., Cory, S., Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348 (1990), 331–333.
42. [42] Harris, A.W., Pinkert, C.A., Crawford, M., Langdon, W.Y., Brinster, R.L., Adams, J.M., The Eμ-myc transgenic mouse: a model for high-incidence spontaneous lymphoma and leukemia of early B cells. J. Exp. Med. 167 (1988), 353–371.
43. [43] Adams, J.M., Harris, A.W., Pinkert, C.A., Corcoran, L.M., Alexander, W.S., Cory, S., Palmiter, R.D., Brinster, R.L., The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318 (1985), 533–538.
44. [44] Soini, Y., Pääkkö, P., Lehto, V.-P., Histopathological evaluation of apoptosis in cancer. Am. J. Pathol. 153 (1998), 1041–1053.
45. [45] Tsujimoto, Y., Cossman, J., Jaffe, E., Croce, C.M., Involvement of the bcl-2 gene in human follicular lymphoma. Science 228 (1985), 1440–1443.
46. [46] Hardwick, J.M., Soane, L., Multiple functions of BCL-2 family proteins. Cold Spring Harb. Perspect. Biol., 5, 2013.
47. [47] Green, D.R., Kroemer, G., The pathophysiology of mitochondrial cell death. Science 305 (2004), 626–629.
48. [48] Strasser, A., O'Connor, L., Dixit, V.M., Apoptosis signaling. Ann. Rev. Biochem. 69 (2000), 217–245.
49. [49] Verhagen, A.M., Ekert, P.G., Pakusch, M., Silke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J., Vaux, D.L., Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing inhibitor of apoptosis (IAP) proteins. Cell 102 (2000), 43–53.
50. [50] Du, C., Fang, M., Li, Y., Li, L., Wang, X., Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102 (2000), 33–42.
51. [51] Kluck, R.M., Bossy-Wetzel, E., Green, D.R., Newmeyer, D.D., The release of cytochrome c from mitochondria - a primary site for Bcl-2 regulation of apoptosis. Science 275 (1997), 1132–1136.
52. [52] Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S., Wang, X., Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade. Cell 91 (1997), 479–489.
53. [53] Liu, X., Kim, C.N., Yang, J., Jemmerson, R., Wang, X., Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86 (1996), 147–157.
54. [54] Wei, M.C., Zong, W.X., Cheng, E.H., Lindsten, T., Panoutsakopoulou, V., Ross, A.J., Roth, K.A., MacGregor, G.R., Thompson, C.B., Korsmeyer, S.J., Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292 (2001), 727–730.
55. [55] Wei, M.C., Lindsten, T., Mootha, V.K., Weiler, S., Gross, A., Ashiya, M., Thompson, C.B., Korsmeyer, S.J., tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14 (2000), 2060–2071.
56. [56] Czabotar, P.E., Westphal, D., Dewson, G., Ma, S., Hockings, C., Fairlie, W.D., Lee, E.F., Yao, S., Robin, A.Y., Smith, B.J., Huang, D.C., Kluck, R.M., Adams, J.M., Colman, P.M., Bax crystal structures reveal how BH3 domains activate bax and nucleate its oligomerization to induce apoptosis. Cell 152 (2013), 519–531.
57. [57] Moldoveanu, T., Grace, C.R., Llambi, F., Nourse, A., Fitzgerald, P., Gehring, K., Kriwacki, R.W., Green, D.R., BID-induced structural changes in BAK promote apoptosis. Nat. Struct. Mol. Biol. 20 (2013), 589–597.
58. [58] Kim, H., Tu, H.C., Ren, D., Takeuchi, O., Jeffers, J.R., Zambetti, G.P., Hsieh, J.J., Cheng, E.H., Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol. Cell 36 (2009), 487–499.
59. [59] Ren, D., Tu, H.C., Kim, H., Wang, G.X., Bean, G.R., Takeuchi, O., Jeffers, J.R., Zambetti, G.P., Hsieh, J.J., Cheng, E.H., BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330 (2010), 1390–1393.
60. [60] Lindsten, T., Ross, A.J., King, A., Zong, W., Rathmell, J.C., Shiels, H.A., Ulrich, E., Waymire, K.G., Mahar, P., Frauwirth, K., Chen, Y., Wei, M., Eng, V.M., Adelman, D.M., Simon, M.C., Ma, A., Golden, J.A., Evan, G., Korsmeyer, S.J., MacGregor, G.R., Thompson, C.B., The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol. Cell 6 (2000), 1389–1399.
61. [61] 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 (2016), 973–988.
62. [62] Leber, B., Lin, J., Andrews, D.W., Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 12 (2007), 897–911.
63. [63] Dewson, G., Kluck, R.M., Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J. Cell. Sci. 122 (2009), 2801–2808.
64. [64] Llambi, F., Moldoveanu, T., Tait, S.W.G., Bouchier-Hayes, L., Temirov, J., McCormick, L.L., Dillon, C.P., Green, D.R., A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol. Cell 44 (2011), 517–531.
65. [65] Westphal, D., Kluck, R.M., Dewson, G., Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell. Death Differ. 21 (2014), 196–205.
66. [66] Ke, F., Bouillet, P., Kaufmann, T., Strasser, A., Kerr, J., Voss, A.K., Consequences of the combined loss of BOK and BAK or BOK and BAX. Cell. Death Dis., 4, 2013, e650.
67. [67] Ke, F., Voss, A., Kerr, J.B., O'Reilly, L.A., Tai, L., Echeverry, N., Bouillet, P., Strasser, A., Kaufmann, T., BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice. Cell. Death Differ. 19 (2012), 915–925.
68. [68] Llambi, F., Wang, Y.M., Victor, B., Yang, M., Schneider, D.M., Gingras, S., Parsons, M.J., Zheng, J.H., Brown, S.A., Pelletier, S., Moldoveanu, T., Chen, T., Green, D.R., BOK is a non-canonical BCL-2 family effector of apoptosis regulated by ER-associated degradation. Cell 165 (2016), 421–433.
69. [69] Petros, A.M., Olejniczak, E.T., Fesik, S.W., Structural biology of the Bcl-2 family of proteins. Biochim. Biophys. Acta 1644 (2004), 83–94.
70. L-Bak peptide complex: recognition between regulators of apoptosis. Science 275 (1997), 983–986.
71. L/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci. 9 (2000), 2528–2534.
72. [72] Chen, L., Willis, S.N., Wei, A., Smith, B.J., Fletcher, J.I., Hinds, M.G., Colman, P.M., Day, C.L., Adams, J.M., Huang, D.C.S., Differential targeting of pro-survival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17 (2005), 393–403.
73. [73] Villunger, A., Michalak, E.M., Coultas, L., Mullauer, F., Bock, G., Ausserlechner, M.J., Adams, J.M., Strasser, A., p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302 (2003), 1036–1038.
74. [74] Bouillet, P., Metcalf, D., Huang, D.C.S., Tarlinton, D.M., Kay, T.W.H., Köntgen, F., Adams, J.M., Strasser, A., Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286 (1999), 1735–1738.
75. [75] Oliver, C.L., Miranda, M.B., Shangary, S., Land, S., Wang, S., Johnson, D.E., (-)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-X(L)-mediated apoptosis resistance. Mol. Cancer Ther. 4 (2005), 23–31.
76. [76] Mohammad, R.M., Wang, S., Aboukameel, A., Chen, B., Wu, X., Chen, J., Al-Katib, A., Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. Mol. Cancer Ther. 4 (2005), 13–21.
77. [77] van Delft, M.F., Wei, A.H., Mason, K.D., Vandenberg, C.J., Chen, L., Czabotar, P.E., Willis, S.N., Scott, C.L., Day, C.L., Cory, S., Adams, J.M., Roberts, A.W., Huang, D.C., 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 (2006), 389–399.
78. [78] Zong, W.X., Lindsten, T., Ross, A.J., MacGregor, G.R., Thompson, C.B., BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 15 (2001), 1481–1486.
79. L sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8 (2001), 705–711.
80. [80] Baggstrom, M.Q., Qi, Y., Koczywas, M., Argiris, A., Johnson, E.A., Millward, M.J., Murphy, S.C., Erlichman, C., Rudin, C.M., Govindan, R., Mayo Phase, C., California, C., A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J. Thorac. Oncol. 6 (2011), 1757–1760.
81. [81] Konopleva, M., Watt, J., Contractor, R., Tsao, T., Harris, D., Estrov, Z., Bornmann, W., Kantarjian, H., Viallet, J., Samudio, I., Andreeff, M., Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res. 68 (2008), 3413–3420.
82. [82] Perez-Galan, P., Roue, G., Villamor, N., Campo, E., Colomer, D., The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 109 (2007), 4441–4449.
83. [83] Schimmer, A.D., O'Brien, S., Kantarjian, H., Brandwein, J., Cheson, B.D., Minden, M.D., Yee, K., Ravandi, F., Giles, F., Schuh, A., Gupta, V., Andreeff, M., Koller, C., Chang, H., Kamel-Reid, S., Berger, M., Viallet, J., Borthakur, G., A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin. Cancer Res. 14 (2008), 8295–8301.
84. [84] O'Brien, S.M., Claxton, D.F., Crump, M., Faderl, S., Kipps, T., Keating, M.J., Viallet, J., Cheson, B.D., Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 113 (2009), 299–305.
85. [85] Paik, P.K., Rudin, C.M., Brown, A., Rizvi, N.A., Takebe, N., Travis, W., James, L., Ginsberg, M.S., Juergens, R., Markus, S., Tyson, L., Subzwari, S., Kris, M.G., Krug, L.M., A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. Cancer Chemother. Pharmacol. 66 (2010), 1079–1085.
86. [86] Paik, P.K., Rudin, C.M., Pietanza, M.C., Brown, A., Rizvi, N.A., Takebe, N., Travis, W., James, L., Ginsberg, M.S., Juergens, R., Markus, S., Tyson, L., Subzwari, S., Kris, M.G., Krug, L.M., A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer 74 (2011), 481–485.
87. [87] Oki, Y., Copeland, A., Hagemeister, F., Fayad, L.E., Fanale, M., Romaguera, J., Younes, A., Experience with obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma. Blood 119 (2012), 2171–2172.
88. [88] Oltersdorf, T., Elmore, S.W., Shoemaker, A.R., Armstrong, R.C., Augeri, D.J., Belli, B.A., Bruncko, M., Deckwerth, T.L., Dinges, J., Hajduk, P.J., Joseph, M.K., Kitada, S., Korsmeyer, S.J., Kunzer, A.R., Letai, A., Li, C., Mitten, M.J., Nettesheim, D.G., Ng, S., Nimmer, P.M., O'Connor, J.M., Oleksijew, A., Petros, A.M., Reed, J.C., Shen, W., Tahir, S.K., Thompson, C.B., Tomaselli, K.J., Wang, B., Wendt, M.D., Zhang, H., Fesik, S.W., Rosenberg, S.H., An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435 (2005), 677–681.
89. [89] Kuroda, J., Kimura, S., Andreeff, M., Ashihara, E., Kamitsuji, Y., Yokota, A., Kawata, E., Takeuchi, M., Tanaka, R., Murotani, Y., Matsumoto, Y., Tanaka, H., Strasser, A., Maekawa, T., ABT-737 is a useful component of combinatory chemotherapies for chronic myelogenous leukaemias with diverse drug resistance mechanisms. Br. J. Haematol. 140 (2008), 181–190.
90. [90] Cragg, M.S., Jansen, E.S., Cook, M., Harris, C., Strasser, A., Scott, C.L., Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J. Clin. Invest 118 (2008), 3651–3659.
91. [91] Cragg, M.S., Kuroda, J., Puthalakath, H., Huang, D.C.S., Strasser, A., Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires bim and can Be enhanced by BH3 mimetics. PLoS Med. 4 (2007), 1681–1689.
92. [92] Cragg, M.S., Harris, C., Strasser, A., Scott, C.L., Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat. Rev. Cancer 9 (2009), 321–326.
93. [93] Tse, C., Shoemaker, A.R., Adickes, J., Anderson, M.G., Chen, J., Jin, S., Johnson, E.F., Marsh, K.C., Mitten, M.J., Nimmer, P., Roberts, L., Tahir, S.K., Xiao, Y., Yang, X., Zhang, H., Fesik, S., Rosenberg, S.H., Elmore, S.W., ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68 (2008), 3421–3428.
94. [94] Roberts, A.W., Seymour, J.F., Brown, J.R., Wierda, W.G., Kipps, T.J., Khaw, S.L., Carney, D.A., He, S.Z., Huang, D.C., Xiong, H., Cui, Y., Busman, T.A., McKeegan, E.M., Krivoshik, A.P., Enschede, S.H., Humerickhouse, R., 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. Of. J. Am. Soc. Clin. Oncol. 30 (2012), 488–496.
95. [95] Wilson, W.H., O'Connor, O.A., Czuczman, M.S., LaCasce, A.S., Gerecitano, J.F., Leonard, J.P., Tulpule, A., Dunleavy, K., Xiong, H., Chiu, Y.L., Cui, Y., Busman, T., Elmore, S.W., Rosenberg, S.H., Krivoshik, A.P., Enschede, S.H., Humerickhouse, R.A., 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 (2010), 1149–1159.
96. [96] Gandhi, L., Camidge, D.R., Ribeiro de Oliveira, M., Bonomi, P., Gandara, D., Khaira, D., Hann, C.L., McKeegan, E.M., Litvinovich, E., Hemken, P.M., Dive, C., Enschede, S.H., Nolan, C., Chiu, Y.L., Busman, T., Xiong, H., Krivoshik, A.P., Humerickhouse, R., Shapiro, G.I., Rudin, C.M., 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. Of. J. Am. Soc. Clin. Oncol. 29 (2011), 909–916.
97. [97] Shoemaker, A.R., Mitten, M.J., Adickes, J., Ackler, S., Refici, M., Ferguson, D., Oleksijew, A., O'Connor, J.M., Wang, B., Frost, D.J., Bauch, J., Marsh, K., Tahir, S.K., Yang, X., Tse, C., Fesik, S.W., Rosenberg, S.H., Elmore, S.W., Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin. Cancer Res. 14 (2008), 3268–3277.
98. [98] Rudin, C.M., Hann, C.L., Garon, E.B., Ribeiro de Oliveira, M., Bonomi, P.D., Camidge, D.R., Chu, Q., Giaccone, G., Khaira, D., Ramalingam, S.S., Ranson, M.R., Dive, C., McKeegan, E.M., Chyla, B.J., Dowell, B.L., Chakravartty, A., Nolan, C.E., Rudersdorf, N., Busman, T.A., Mabry, M.H., Krivoshik, A.P., Humerickhouse, R.A., Shapiro, G.I., Gandhi, L., Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin. Cancer Res. 18 (2012), 3163–3169.
99. [99] Cleary, J.M., Lima, C.M., Hurwitz, H.I., Montero, A.J., Franklin, C., Yang, J., Graham, A., Busman, T., Mabry, M., Holen, K., Shapiro, G.I., Uronis, H., A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors. Invest New Drugs 32 (2014), 937–945.
100. [100] Phillips, D.C., Xiao, Y., Lam, L.T., Litvinovich, E., Roberts-Rapp, L., Souers, A.J., Leverson, J.D., Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J., 5, 2015, e368.
101. [101] Roberts, A.W., Davids, M.S., Pagel, J.M., Kahl, B.S., Puvvada, S.D., Gerecitano, J.F., Kipps, T.J., Anderson, M.A., Brown, J.R., Gressick, L., Wong, S., Dunbar, M., Zhu, M., Desai, M.B., Cerri, E., Heitner Enschede, S., Humerickhouse, R.A., Wierda, W.G., Seymour, J.F., Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374 (2016), 311–322.
102. [102] Tolcher, A.W., LoRusso, P., Arzt, J., Busman, T.A., Lian, G., Rudersdorf, N.S., Vanderwal, C.A., Kirschbrown, W., Holen, K.D., Rosen, L.S., Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 76 (2015), 1025–1032.
103. [103] Tolcher, A.W., LoRusso, P., Arzt, J., Busman, T.A., Lian, G., Rudersdorf, N.S., Vanderwal, C.A., Waring, J.F., Yang, J., Holen, K.D., Rosen, L.S., Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study. Cancer Chemother. Pharmacol. 76 (2015), 1041–1049.
104. [104] Mason, K.D., Carpinelli, M.R., Fletcher, J.I., Collinge, J.E., Hilton, A.A., Ellis, S., Kelly, P.N., Ekert, P.G., Metcalf, D., Roberts, A.W., Huang, D.C., Kile, B.T., Programmed a nuclear cell death delimits platelet life span. Cell 128 (2007), 1173–1186.
105. [105] Wagner, K.U., Claudio, E., Rucker, E.B. 3rd, Riedlinger, G., Broussard, C., Schwartzberg, P.L., Siebenlist, U., Hennighausen, L., Conditional deletion of the Bcl-x gene from erythroid cells results in hemolytic anemia and profound splenomegaly. Development 127 (2000), 4949–4958.
106. [106] Souers, A.J., Leverson, J.D., Boghaert, E.R., Ackler, S.L., Catron, N.D., Chen, J., Dayton, B.D., Ding, H., Enschede, S.H., Fairbrother, W.J., Huang, D.C., Hymowitz, S.G., Jin, S., Khaw, S.L., Kovar, P.J., Lam, L.T., Lee, J., Maecker, H.L., Marsh, K.C., Mason, K.D., Mitten, M.J., Nimmer, P.M., Oleksijew, A., Park, C.H., Park, C.M., Phillips, D.C., Roberts, A.W., Sampath, D., Seymour, J.F., Smith, M.L., Sullivan, G.M., Tahir, S.K., Tse, C., Wendt, M.D., Xiao, Y., Xue, J.C., Zhang, H., Humerickhouse, R.A., Rosenberg, S.H., Elmore, S.W., ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19 (2013), 202–208.
107. [107] Vogler, M., Dinsdale, D., Dyer, M.J., Cohen, G.M., ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br. J. Haematol. 163 (2013), 139–142.
108. [108] Anderson, M.A., Deng, J., Seymour, J.F., Tam, C., Kim, S.Y., Fein, J., Yu, L., Brown, J.R., Westerman, D., Si, E.G., Majewski, I.J., Segal, D., Heitner Enschede, S.L., Huang, D.C., Davids, M.S., Letai, A., Roberts, A.W., The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 127 (2016), 3215–3224.
109. [109] Landau, D.A., Carter, S.L., Stojanov, P., McKenna, A., Stevenson, K., Lawrence, M.S., Sougnez, C., Stewart, C., Sivachenko, A., Wang, L., Wan, Y., Zhang, W., Shukla, S.A., Vartanov, A., Fernandes, S.M., Saksena, G., Cibulskis, K., Tesar, B., Gabriel, S., Hacohen, N., Meyerson, M., Lander, E.S., Neuberg, D., Brown, J.R., Getz, G., Wu, C.J., Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152 (2013), 714–726.
110. [110] High, L.M., Szymanska, B., Wilczynska-Kalak, U., Barber, N., O'Brien, R., Khaw, S.L., Vikstrom, I.B., Roberts, A.W., Lock, R.B., The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs. Mol. Pharmacol. 77 (2010), 483–494.
111. [111] Bate-Eya, L.T., den Hartog, I.J., van der Ploeg, I., Schild, L., Koster, J., Santo, E.E., Westerhout, E.M., Versteeg, R., Caron, H.N., Molenaar, J.J., Dolman, M.E., High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. Oncotarget 7 (2016), 27946–27958.
112. [112] Rooswinkel, R.W., van de Kooij, B., Verheij, M., Borst, J., Bcl-2 is a better ABT-737 target than Bcl-xL or Bcl-w and only Noxa overcomes resistance mediated by Mcl-1, Bfl-1, or Bcl-B. Cell. Death Dis., 3, 2012, e366.
113. [113] Merino, D., Khaw, S.L., Glaser, S.P., Anderson, D.J., Belmont, L.D., Wong, C., Yue, P., Robati, M., Phipson, B., Fairlie, W.D., Lee, E.F., Campbell, K.J., Vandenberg, C.J., Cory, S., Roberts, A.W., Ludlam, M.J., Huang, D.C., Bouillet, P., Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood 119 (2012), 5807–5816.
114. [114] Yecies, D., Carlson, N.E., Deng, J., Letai, A., Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 115 (2010), 3304–3313.
115. [115] Ni Chonghaile, T., Sarosiek, K.A., Vo, T.T., Ryan, J.A., Tammareddi, A., Moore Vdel, G., Deng, J., Anderson, K.C., Richardson, P., Tai, Y.T., Mitsiades, C.S., Matulonis, U.A., Drapkin, R., Stone, R., Deangelo, D.J., McConkey, D.J., Sallan, S.E., Silverman, L., Hirsch, M.S., Carrasco, D.R., Letai, A., Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334 (2011), 1129–1133.
116. [116] Wolter, K.G., Hsu, Y.T., Smith, C.L., Nechushtan, A., Xi, X.G., Youle, R.J., Movement of Bax from the cytosol to mitochondria during apoptosis. J. Cell. Biol. 139 (1997), 1281–1292.
117. [117] Al-Harbi, S., Hill, B.T., Mazumder, S., Singh, K., Devecchio, J., Choudhary, G., Rybicki, L.A., Kalaycio, M., Maciejewski, J.P., Houghton, J.A., Almasan, A., An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737. Blood 118 (2011), 3579–3590.
118. [118] Glaser, S.P., Lee, E.F., Trounson, E., Bouillet, P., Wei, A., Fairlie, W.D., Izon, D.J., Zuber, J., Rappaport, A.R., Herold, M.J., Alexander, W.S., Lowe, S.W., Robb, L., Strasser, A., Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 26 (2012), 120–125.
119. [119] Kelly, G.L., Grabow, S., Glaser, S.P., Fitzsimmons, L., Aubrey, B.J., Okamoto, T., Valente, L.J., Robati, M., Tai, L., Fairlie, W.D., Lee, E.F., Lindstrom, M.S., Wiman, K.G., Huang, D.C., Bouillet, P., Rowe, M., Rickinson, A.B., Herold, M.J., Strasser, A., Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev. 28 (2014), 58–70.
120. [120] Koss, B., Morrison, J., Perciavalle, R.M., Singh, H., Rehg, J.E., Williams, R.T., Opferman, J.T., Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia. Blood 122 (2013), 1587–1598.
121. [121] Grabow, S., Delbridge, A.R., Valente, L.J., Strasser, A., MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice. Blood 124 (2014), 3939–3946.
122. [122] Bruncko, M., Wang, L., Sheppard, G.S., Phillips, D.C., Tahir, S.K., Xue, J., Erickson, S., Fidanze, S., Fry, E., Hasvold, L., Jenkins, G.J., Jin, S., Judge, R.A., Kovar, P.J., Madar, D., Nimmer, P., Park, C., Petros, A.M., Rosenberg, S.H., Smith, M.L., Song, X., Sun, C., Tao, Z.F., Wang, X., Xiao, Y., Zhang, H., Tse, C., Leverson, J.D., Elmore, S.W., Souers, A.J., Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J. Med. Chem. 58 (2015), 2180–2194.
123. [123] Leverson, J.D., Zhang, H., Chen, J., Tahir, S.K., Phillips, D.C., Xue, J., Nimmer, P., Jin, S., Smith, M., Xiao, Y., Kovar, P., Tanaka, A., Bruncko, M., Sheppard, G.S., Wang, L., Gierke, S., Kategaya, L., Anderson, D.J., Wong, C., Eastham-Anderson, J., Ludlam, M.J., Sampath, D., Fairbrother, W.J., Wertz, I., Rosenberg, S.H., Tse, C., Elmore, S.W., Souers, A.J., 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, 2015, e1590.
124. [124] Xiao, Y., Nimmer, P., Sheppard, G.S., Bruncko, M., Hessler, P., Lu, X., Roberts-Rapp, L., Pappano, W.N., Elmore, S.W., Souers, A.J., Leverson, J.D., Phillips, D.C., MCL-1 is a key determinant of breast Cancer cell survival: validation of MCL-1 dependency utilizing a highly selective small molecule inhibitor. Mol. Cancer Ther. 14 (2015), 1837–1847.
125. [125] Phillips, D.C., Xiao, Y., Lam, L.T., Litvinovich, E., Roberts-Rapp, L., Souers, A.J., Leverson, J.D., Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J., 6, 2016, e403.
126. [126] Punnoose, E.A., Leverson, J.D., Peale, F., Boghaert, E.R., Belmont, L.D., Tan, N., Young, A., Mitten, M., Ingalla, E., Darbonne, W.C., Oleksijew, A., Tapang, P., Yue, P., Oeh, J., Lee, L., Maiga, S., Fairbrother, W.J., Amiot, M., Souers, A.J., Sampath, D., Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol. Cancer Ther. 15 (2016), 1132–1144.
127. [127] Rinkenberger, J.L., Horning, S., Klocke, B., Roth, K., Korsmeyer, S.J., Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev. 14 (2000), 23–27.
128. [128] Opferman, J.T., Letai, A., Beard, C., Sorcinelli, M.D., Ong, C.C., Korsmeyer, S.J., Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426 (2003), 671–676.
129. [129] Peperzak, V., Vikstrom, I., Walker, J., Glaser, S.P., LePage, M., Coquery, C.M., Erickson, L.D., Fairfax, K., Mackay, F., Strasser, A., Nutt, S.L., Tarlinton, D.M., Mcl-1 is essential for the survival of plasma cells. Nat. Immunol. 14 (2013), 290–297.
130. [130] Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A.L., Toumelin-Braizat, G.L., Chanrion, M., Kelly, G.L., Gong, J.-N., Moujalled, D., Bruno, A., Csekei, M., Paczal, A., Szabo, Z., Sipos, S., Radics, G., Proszenyak, A., Balint, B., Ondi, L., Blasko, G., Robertson, A., Surgenor, A., Dokurno, P., Chen, I., Matassova, N., Smith, J., Pedder, C., Graham, C., Studeny, A., Lysiak-Auvity, G., Girard, A.-M., Gravé, F., Segal, D., Riffkin, C.D., Pomilio, G., Galbraith, L.C.A., Aubrey, B.J., Brennan, M.S., Herold, M.J., Chang, C., Guasconi, G., Cauquil, N., Melchiore, F., Guigal-Stephan, N., Lockhart, B., Colland, F., Hickman, J.A., Roberts, A.W., Huang, D.C.S., Wei, A.H., Strasser, A., Lessene, G., Geneste, O., The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature, 2016 Published online 19/10/16.
131. [131] Beroukhim, R., Mermel, C.H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J.S., Dobson, J., Urashima, M., Mc Henry, K.T., Pinchback, R.M., Ligon, A.H., Cho, Y.J., Haery, L., Greulich, H., Reich, M., Winckler, W., Lawrence, M.S., Weir, B.A., Tanaka, K.E., Chiang, D.Y., Bass, A.J., Loo, A., Hoffman, C., Prensner, J., Liefeld, T., Gao, Q., Yecies, D., Signoretti, S., Maher, E., Kaye, F.J., Sasaki, H., Tepper, J.E., Fletcher, J.A., Tabernero, J., Baselga, J., Tsao, M.S., Demichelis, F., Rubin, M.A., Janne, P.A., Daly, M.J., Nucera, C., Levine, R.L., Ebert, B.L., Gabriel, S., Rustgi, A.K., Antonescu, C.R., Ladanyi, M., Letai, A., Garraway, L.A., Loda, M., Beer, D.G., True, L.D., Okamoto, A., Pomeroy, S.L., Singer, S., Golub, T.R., Lander, E.S., Getz, G., Sellers, W.R., Meyerson, M., The landscape of somatic copy-number alteration across human cancers. Nature 463 (2010), 899–905.
132. [132] Amundson, S.A., Myers, T.G., Scudiero, D., Kitada, S., Reed, J.C., Fornace, A.J. Jr., An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60 (2000), 6101–6110.
133. [133] Lessene, G., Czabotar, P.E., Sleebs, B.E., Zobel, K., Lowes, K.N., Adams, J.M., Baell, J.B., Colman, P.M., Deshayes, K., Fairbrother, W.J., Flygare, J.A., Gibbons, P., Kersten, W.J., Kulasegaram, S., Moss, R.M., Parisot, J.P., Smith, B.J., Street, I.P., Yang, H., Huang, D.C., Watson, K.G., Structure-guided design of a selective BCL-X(L) inhibitor. Nat. Chem. Biol. 9 (2013), 390–397.
134. [134] Brady, R.M., Vom, A., Roy, M.J., Toovey, N., Smith, B.J., Moss, R.M., Hatzis, E., Huang, D.C., Parisot, J.P., Yang, H., Street, I.P., Colman, P.M., Czabotar, P.E., Baell, J.B., Lessene, G., De-novo designed library of benzoylureas as inhibitors of BCL-XL: synthesis, structural and biochemical characterization. J. Med. Chem. 57 (2014), 1323–1343.
135. [135] Leverson, J.D., Phillips, D.C., Mitten, M.J., Boghaert, E.R., Diaz, D., Tahir, S.K., Belmont, L.D., Nimmer, P., Xiao, Y., Ma, X.M., Lowes, K.N., Kovar, P., Chen, J., Jin, S., Smith, M., Xue, J., Zhang, H., Oleksijew, A., Magoc, T.J., Vaidya, K.S., Albert, D.H., Tarrant, J.M., La, N., Wang, L., Tao, Z.F., Wendt, M.D., Sampath, D., Rosenberg, S.H., Tse, C., Huang, D.C., Fairbrother, W.J., Elmore, S.W., Souers, A.J., Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci. Transl. Med., 7, 2015, 279ra240.
136. [136] Morales, A.A., Olsson, A., Celsing, F., Osterborg, A., Jondal, M., Osorio, L.M., High expression of bfl-1 contributes to the apoptosis resistant phenotype in B-cell chronic lymphocytic leukemia. Int. J. Cancer 113 (2005), 730–737.
137. [137] Olsson, A., Norberg, M., Okvist, A., Derkow, K., Choudhury, A., Tobin, G., Celsing, F., Osterborg, A., Rosenquist, R., Jondal, M., Osorio, L.M., Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia. Br. J. Cancer 97 (2007), 769–777.
138. [138] Park, I.C., Lee, S.H., Whang, D.Y., Hong, W.S., Choi, S.S., Shin, H.S., Choe, T.B., Hong, S.I., Expression of a novel Bcl-2 related gene, Bfl-1, in various human cancers and cancer cell lines. Anticancer Res. 17 (1997), 4619–4622.
139. [139] Riker, A.I., Enkemann, S.A., Fodstad, O., Liu, S., Ren, S., Morris, C., Xi, Y., Howell, P., Metge, B., Samant, R.S., Shevde, L.A., Li, W., Eschrich, S., Daud, A., Ju, J., Matta, J., The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis. BMC Med. Genomics, 1, 2008, 13.
140. [140] Lin, E.Y., Orlofsky, A., Berger, M.S., Prystowsky, M.B., Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J. Immunol. 151 (1993), 1979–1988.
141. [141] Vogler, M., BCL2A1: the underdog in the BCL2 family. Cell. Death Differ. 19 (2012), 67–74.
142. [142] Mathieu, A.L., Sperandio, O., Pottiez, V., Balzarin, S., Herledan, A., Elkaim, J.O., Fogeron, M.L., Piveteau, C., Dassonneville, S., Deprez, B., Villoutreix, B.O., Bonnefoy, N., Leroux, F., Identification of small inhibitory molecules targeting the Bfl-1 anti-apoptotic protein that alleviates resistance to ABT-737. J. Biomol. Screen 19 (2014), 1035–1046.
143. [143] Walensky, L.D., Pitter, K., Morash, J., Oh, K.J., Barbuto, S., Fisher, J., Smith, E., Verdine, G.L., Korsmeyer, S.J., A stapled BID BH3 helix directly binds and activates BAX. Mol. Cell 24 (2006), 199–210.
144. [144] Gavathiotis, E., Suzuki, M., Davis, M.L., Pitter, K., Bird, G.H., Katz, S.G., Tu, H.C., Kim, H., Cheng, E.H., Tjandra, N., Walensky, L.D., BAX activation is initiated at a novel interaction site. Nature 455 (2008), 1076–1081.
145. [145] Walensky, L.D., Kung, A.L., Escher, I., Malia, T.J., Barbuto, S., Wright, R.D., Wagner, G., Verdine, G.L., Korsmeyer, S.J., Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305 (2004), 1466–1470.
146. [146] Okamoto, T., Zobel, K., Fedorova, A., Quan, C., Yang, H., Fairbrother, W.J., Huang, D.C., Smith, B.J., Deshayes, K., Czabotar, P.E., Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity. ACS Chem. Biol. 8 (2013), 297–302.
147. [147] Gavathiotis, E., Reyna, D.E., Bellairs, J.A., Leshchiner, E.S., Walensky, L.D., Direct and selective small-molecule activation of proapoptotic BAX. Nat. Chem. Biol. 8 (2012), 639–645.
148. [148] Xin, M., Li, R., Xie, M., Park, D., Owonikoko, T.K., Sica, G.L., Corsino, P.E., Zhou, J., Ding, C., White, M.A., Magis, A.T., Ramalingam, S.S., Curran, W.J., Khuri, F.R., Deng, X., Small-molecule Bax agonists for cancer therapy. Nat. Commun., 5, 2014, 4935.
149. [149] Zhao, G., Zhu, Y., Eno, C.O., Liu, Y., Deleeuw, L., Burlison, J.A., Chaires, J.B., Trent, J.O., Li, C., Activation of the proapoptotic Bcl-2 protein Bax by a small molecule induces tumor cell apoptosis. Mol. Cell. Biol. 34 (2014), 1198–1207.
150. [150] Iyer, S., Anwari, K., Alsop, A.E., Yuen, W.S., Huang, D.C., Carroll, J., Smith, N.A., Smith, B.J., Dewson, G., Kluck, R.M., Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies. Nat. Commun., 7, 2016, 11734.
151. [151] Marschall, A.L., Dubel, S., Boldicke, T., Specific in vivo knockdown of protein function by intrabodies. MAbs 7 (2015), 1010–1035.
152. [152] Han, B., Park, D., Li, R., Xie, M., Owonikoko, T.K., Zhang, G., Sica, G.L., Ding, C., Zhou, J., Magis, A.T., Chen, Z.G., Shin, D.M., Ramalingam, S.S., Khuri, F.R., Curran, W.J., Deng, X., Small-molecule Bcl2 BH4 antagonist for lung Cancer therapy. Cancer Cell 27 (2015), 852–863.
153. [153] Cheng, E.H., Sheiko, T.V., Fisher, J.K., Craigen, W.J., Korsmeyer, S.J., VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301 (2003), 513–517.
154. [154] Ma, S.B., Nguyen, T.N., Tan, I., Ninnis, R., Iyer, S., Stroud, D.A., Menard, M., Kluck, R.M., Ryan, M.T., Dewson, G., Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: a requirement for VDAC2 or Bak for efficient Bax apoptotic function. Cell. Death Differ. 21 (2014), 1925–1935.
155. [155] Karbowski, M., Lee, Y.J., Gaume, B., Jeong, S.Y., Frank, S., Nechushtan, A., Santel, A., Fuller, M., Smith, C.L., Youle, R.J., Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J. Cell. Biol. 159 (2002), 931–938.
156. L, an inhibitor of programmed cell death. Nature 381 (1996), 335–341.
157. [157] Lee, E.F., Czabotar, P.E., Smith, B.J., Deshayes, K., Zobel, K., Colman, P.M., Fairlie, W.D., Crystal structure of ABT-737 complexed with Bcl-x(L): implications for selectivity of antagonists of the Bcl-2 family. Cell. Death Differ. 14 (2007), 1711–1713.
158. [158] Nguyen, M., Marcellus, R.C., Roulston, A., et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1–mediated resistance to apoptosis. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 19512–19517.