Cell death and the mitochondria: Therapeutic targeting of the BCL-2 family-driven pathway

British Journal of Pharmacology

Volumn 171, Issue 8, 2014, Pages 1973-1987

  Roy, M J ^a,b   Vom, A ^a,b   Czabotar, P E ^a,b   Lessene, G ^a,b  

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

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

apoptosis; BCL 2 family; cancer; neurodegenerative diseases; protein protein interactions

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; BH3 PROTEIN; BI 97C1; CASPASE; CYTOCHROME C; GOSSYPOL; ISOSORBIDE; NAVITOCLAX; OBATOCLAX; PROTEIN BAK; PROTEIN BAX; PROTEIN BCL 2; SABUTOCLAX; UNCLASSIFIED DRUG; PEPTIDE; SULFONAMIDE;

APOPTOSIS; B CELL LYMPHOMA; CELL DEATH; CELL FATE; CELL ORGANELLE; CYTOPLASM; DRUG STRUCTURE; ENERGY RESOURCE; HOMEOSTASIS; MEMBRANE PERMEABILITY; MITOCHONDRIAL MEMBRANE; MITOCHONDRION; OUTER MEMBRANE; PHYSIOLOGICAL STRESS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN FAMILY; PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; ANTAGONISTS AND INHIBITORS; BIOLOGICAL MODEL; DRUG DEVELOPMENT; DRUG EFFECTS; HUMAN; MOLECULARLY TARGETED THERAPY; PHYSIOLOGY; PROCEDURES; PROTEIN TERTIARY STRUCTURE; SIGNAL TRANSDUCTION;

CELL DEATH; DRUG DISCOVERY; HUMANS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; PEPTIDES; PROTEIN STRUCTURE, TERTIARY; PROTO-ONCOGENE PROTEINS C-BCL-2; SIGNAL TRANSDUCTION; SULFONAMIDES;

EID: 84897406151     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12431     Document Type: Review

References (142)

1. Adams JM, Cory S, (2007). The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26: 1324-1337.
2. Aguilar A, Zhou H, Chen J, Liu L, Bai L, McEachern D, et al. (2013). A potent and highly efficacious Bcl-2/Bcl-xL inhibitor. J Med Chem 56: 3048-3067.
3. Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC, Fornace AJ Jr, (2000). An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res 60: 6101-6110.
4. Basit F, Cristofanon S, Fulda S, (2013). Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes. Cell Death Differ 20: 1161-1173.
5. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. (2010). The landscape of somatic copy-number alteration across human cancers. Nature 463: 899-905.
6. Bird GH, Bernal F, Pitter K, Walensky LD, (2008). Synthesis and biophysical characterization of stabilized alpha-helices of BCL-2 domains. Methods Enzymol 446: 369-386.
7. Boersma MD, Haase HS, Peterson-Kaufman KJ, Lee EF, Clarke OB, Colman PM, et al. (2012). Evaluation of diverse alpha/beta-backbone patterns for functional alpha-helix mimicry: analogues of the Bim BH3 domain. J Am Chem Soc 134: 315-323.
8. Bombrun A, Gerber P, Casi G, Terradillos O, Antonsson B, Halazy S, (2003). 3,6-dibromocarbazole piperazine derivatives of 2-propanol as first inhibitors of cytochrome c release via Bax channel modulation. J Med Chem 46: 4365-4368.
9. Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, et al. (2002). BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415: 922-926.
10. Bratton SB, Salvesen GS, (2010). Regulation of the Apaf-1-caspase-9 apoptosome. J Cell Sci 123: 3209-3214.
11. Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC, (2003). Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22: 8608-8618.
12. Brown CJ, Quah ST, Jong J, Goh AM, Chiam PC, Khoo KH, et al. (2012). Stapled peptides with improved potency and specificity that activate p53. ACS Chem Biol 8: 506-512.
13. Bruncko M, Song X, Ding H, Tao Z-F, Kunzer AR, (2008). Nonsubstituted indoles as Mcl-1 inhibitors and their preparation, WO-0130970-A1.
14. Campas C, Cosialls AM, Barragan M, Iglesias-Serret D, Santidrian AF, Coll-Mulet L, et al. (2006). Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol 34: 1663-1669.
15. Cantel S, Isaad Ale C, Scrima M, Levy JJ, DiMarchi RD, Rovero P, et al. (2008). Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide-alkyne 1,3-dipolar cycloaddition. J Org Chem 73: 5663-5674.
16. Carrington EM, Vikstrom IB, Light A, Sutherland RM, Londrigan SL, Mason KD, et al. (2010). BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc Natl Acad Sci USA 107: 10967-10971.
17. Cartron PF, Gallenne T, Bougras G, Gautier F, Manero F, Vusio P, et al. (2004). The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA. Mol Cell 16: 807-818.
18. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, et al. (2006). Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9: 351-365.
19. Chen J, Zhou H, Aguilar A, Liu L, Bai L, McEachern D, et al. (2012). Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression. J Med Chem 55: 8502-8514.
20. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, et al. (2005). Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17: 393-403.
21. Chiappori AA, Schreeder MT, Moezi MM, Stephenson JJ, Blakely J, Salgia R, et al. (2012). A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer. Br J Cancer 106: 839-845.
22. Chou JJ, Li H, Salvesen GS, Yuan J, Wagner G, (1999). Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 96: 615-624.
23. Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B, et al. (2012). A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol 19: 1175-1186.
24. Czabotar PE, Lessene G, (2010). Bcl-2 family proteins as therapeutic targets. Curr Pharm Des 16: 3132-3148.
25. Czabotar PE, Lee EF, Thompson GV, Wardak AZ, Fairlie WD, Colman PM, (2011). Mutations to Bax beyond the BH3 domain disrupts interactions with pro-survival proteins and promotes apoptosis. J Biol Chem 286: 7123-7131.
26. Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, et al. (2013). Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 152: 519-531.
27. Dash R, Azab B, Quinn BA, Shen X, Wang X-Y, Das SK, et al. (2011). Apogossypol derivative BI-97C1 (sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc Natl Acad Sci USA 108: 8785-8790.
28. Day CL, Chen L, Richardson SJ, Harrison PJ, Huang DC, Hinds MG, (2005). Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands. J Biol Chem 280: 4738-4744.
29. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A, (2007). Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 117: 112-121.
30. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, et al. (2006). 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.
31. Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A, (2007). BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 12: 171-185.
32. Denisov AY, Madiraju MS, Chen G, Khadir A, Beauparlant P, Attardo G, et al. (2003). Solution structure of human BCL-w: modulation of ligand binding by the C-terminal helix. J Biol Chem 278: 21124-21128.
33. Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, et al. (2008). To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions. Mol Cell 30: 369-380.
34. Dewson G, Ma S, Frederick P, Hockings C, Tan I, Kratina T, et al. (2012). Bax dimerizes via a symmetric BH3:groove interface during apoptosis. Cell Death Differ 19: 661-670.
35. Edlich F, Banerjee S, Suzuki M, Cleland MM, Arnoult D, Wang C, et al. (2011). Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell 145: 104-116.
36. Elmore SW, Souers AJ, Bruncko M, Song X, Wang X, Hasvold LA, et al. (2008). 7-substituted indoles as Mcl-1 protein inhibitors and their preparation, WO-0131000-A2.
37. Friberg A, Vigil D, Zhao B, Daniels RN, Burke JP, Garcia-Barrantes PM, et al. (2013). Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J Med Chem 56: 15-30.
38. Galluzzi L, Morselli E, Kepp O, Kroemer G, (2009). Targeting post-mitochondrial effectors of apoptosis for neuroprotection. Biochim Biophys Acta 1787: 402-413.
39. Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, et al. (2011). 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.
40. Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, et al. (2008). BAX activation is initiated at a novel interaction site. Nature 455: 1076-1081.
41. Gavathiotis E, Reyna DE, Davis ML, Bird GH, Walensky LD, (2010). BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell 40: 481-492.
42. Gavathiotis E, Reyna DE, Bellairs JA, Leshchiner ES, Walensky LD, (2012). Direct and selective small-molecule activation of proapoptotic BAX. Nat Chem Biol 8: 639-645.
43. George NM, Evans JJ, Luo X, (2007). A three-helix homo-oligomerization domain containing BH3 and BH1 is responsible for the apoptotic activity of Bax. Genes Dev 21: 1937-1948.
44. Hanahan D, Weinberg RA, (2000). The hallmarks of cancer. Cell 100: 57-70.
45. Hanahan D, Weinberg RA, (2011). Hallmarks of cancer: the next generation. Cell 144: 646-674.
46. Heist RS, Fain J, Chinnasami B, Khan W, Molina JR, Sequist LV, et al. (2010). Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol 5: 1637-1643.
47. Herman MD, Nyman T, Welin M, Lehtio L, Flodin S, Tresaugues L, et al. (2008). Completing the family portrait of the anti-apoptotic Bcl-2 proteins: crystal structure of human Bfl-1 in complex with Bim. FEBS Lett 582: 3590-3594.
48. Hetz C, Vitte PA, Bombrun A, Rostovtseva TK, Montessuit S, Hiver A, et al. (2005). Bax channel inhibitors prevent mitochondrion-mediated apoptosis and protect neurons in a model of global brain ischemia. J Biol Chem 280: 42960-42970.
49. Hinds MG, Lackmann M, Skea GL, Harrison PJ, Huang DCS, Day CL, (2003). The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity. EMBO J 22: 1497-1507.
50. Hinds MG, Smits C, Fredericks-Short R, Risk JM, Bailey M, Huang DC, et al. (2007). Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ 14: 128-136.
51. Hsu YT, Wolter KG, Youle RJ, (1997). Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci USA 94: 3668-3672.
52. Jackson RS, Placzek W, Fernandez A, Ziaee S, Chu C-Y, Wei J, et al. (2012). Sabutoclax, a Mcl-1 antagonist, inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer. Neoplasia 14: 656-665.
53. Johnson LM, Mortenson DE, Yun HG, Horne WS, Ketas TJ, Lu M, et al. (2012). Enhancement of alpha-helix mimicry by an alpha/beta-peptide foldamer via incorporation of a dense ionic side-chain array. J Am Chem Soc 134: 7317-7320.
54. Juin P, Geneste O, Gautier F, Depil S, Campone M, (2013). Decoding and unlocking the BCL-2 dependency of cancer cells. Nat Rev Cancer 13: 455-465.
55. Kawamoto SA, Coleska A, Ran X, Yi H, Yang CY, Wang S, (2012). Design of triazole-stapled BCL9 alpha-helical peptides to target the beta-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction. J Med Chem 55: 1137-1146.
56. Kerr JF, Wyllie AH, Currie AR, (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239-257.
57. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvalo PP, Kitada S, et al. (2006). Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10: 375-388.
58. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, et al. (2005). BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17: 525-535.
59. Kvansakul M, Yang H, Fairlie WD, Czabotar PE, Fischer SF, Perugini MA, et al. (2008). Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands. Cell Death Differ 15: 1564-1571.
60. Labelle JL, Katz SG, Bird GH, Gavathiotis E, Stewart ML, Lawrence C, et al. (2012). A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Invest 122: 2018-2031.
61. Leber B, Lin J, Andrews DW, (2010). Still embedded together binding to membranes regulates Bcl-2 protein interactions. Oncogene 29: 5221-5230.
62. Lee EF, Czabotar PE, Smith BJ, Deshayes K, Zobel K, Colman PM, et al. (2007). Crystal structure of ABT-737 complexed with Bcl-x(L): implications for selectivity of antagonists of the Bcl-2 family. Cell Death Differ 14: 1711-1713.
63. Lee EF, Smith BJ, Horne WS, Mayer KN, Evangelista M, Colman PM, et al. (2011). Structural basis of Bcl-x(L) recognition by a BH3-mimetic α/β-peptide generated by sequence-based design. ChemBioChem 12: 2025-2032.
64. Leshchiner ES, Braun CR, Bird GH, Walensky LD, (2013). Direct activation of full-length proapoptotic BAK. Proc Natl Acad Sci USA 110: E986-E995.
65. Lessene G, Czabotar PE, Colman PM, (2008). BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 7: 989-1000.
66. Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM, et al. (2013). Structure-guided design of a selective BCL-XL inhibitor. Nat Chem Biol 9: 390-397.
67. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ, (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2: 183-192.
68. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B, (2009). An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 15: 3172-3176.
69. Liu X, Dai S, Zhu Y, Marrack P, Kappler JW, (2003). The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. Immunity 19: 341-352.
70. Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, McCormick LL, et al. (2011). A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell 44: 517-531.
71. Lovell JF, Billen LP, Bindner S, Shamas-Din A, Fradin C, Leber B, et al. (2008). Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135: 1074-1084.
72. Lukiw WJ, Bazan NG, (2010). Inflammatory, apoptotic, and survival gene signaling in Alzheimer's disease. Mol Neurobiol 42: 10-16.
73. Ma S, Hockings C, Anwari K, Kratina T, Fennell S, Lazarou M, et al. (2013). Assembly of the Bak apoptotic pore: a critical role for the Bak alpha6 helix in the multimerization of homodimers during apoptosis. J Biol Chem 288: 26027-26038.
74. McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D, (1999). Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell 96: 625-634.
75. Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, et al. (1994). Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13: 1017-1030.
76. Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, et al. (2007). Programmed anuclear cell death delimits platelet life span. Cell 128: 1173-1186.
77. Mason KD, Khaw SL, Rayeroux KC, Chew E, Lee EF, Fairlie WD, et al. (2009). The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 23: 2034-2041.
78. Mason KD, Lin A, Robb L, Josefsson EC, Henley KJ, Gray DH, et al. (2013). Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease. Proc Natl Acad Sci USA 110: 2599-2604.
79. Merino D, Khaw SL, Glaser SP, Anderson DJ, Belmont LD, Wong C, et al. (2012). Bcl-2, Bcl-xL, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood 119: 5807-5816.
80. Miyashita T, Reed JC, (1993). Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81: 151-157.
81. Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G, Gehring K, (2006). The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell 24: 677-688.
82. Moldoveanu T, Grace CR, Llambi F, Nourse A, Fitzgerald P, Gehring K, et al. (2013). BID-induced structural changes in BAK promote apoptosis. Nat Struct Mol Biol 20: 589-597.
83. Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, et al. (1996). X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381: 335-341.
84. Oh KJ, Singh P, Lee K, Foss K, Lee S, Park M, et al. (2010). Conformational changes in BAK, a pore-forming proapoptotic Bcl-2 family member, upon membrane insertion and direct evidence for the existence of BH3-BH3 contact interface in BAK homo-oligomers. J Biol Chem 285: 28924-28937.
85. Okamoto T, Zobel K, Fedorova A, Quan C, Yang H, Fairbrother WJ, et al. (2013). Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity. ACS Chem Biol 8: 297-302.
86. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677-681.
87. Oltvai ZN, Milliman CL, Korsmeyer SJ, (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609-619.
88. Peixoto PM, Ryu SY, Bombrun A, Antonsson B, Kinnally KW, (2009). MAC inhibitors suppress mitochondrial apoptosis. Biochem J 423: 381-387.
89. Peng Z, Xue B, Kurgan L, Uversky VN, (2013). Resilience of death: intrinsic disorder in proteins involved in the programmed cell death. Cell Death Differ 20: 1257-1267.
90. Perez HL, Banfi P, Bertrand J, Cai Z-W, Grebinski JW, Kim K, et al. (2012). Identification of a phenylacylsulfonamide series of dual Bcl-2/Bcl-xL antagonists. Bioorg Med Chem Lett 22: 3946-3950.
91. Petros AM, Medek A, Nettesheim DG, Kim DH, Yoon HS, Swift K, et al. (2001). Solution structure of the antiapoptotic protein bcl-2. Proc Natl Acad Sci USA 98: 3012-3037.
92. Petros AM, Olejniczak ET, Fesik SW, (2004). Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 1644: 83-94.
93. Petros AM, Dinges J, Augeri DJ, Baumeister SA, Betebenner DA, Bures MG, et al. (2006). Discovery of a potent inhibitor of the antiapoptotic protein Bcl-x(L) from NMR and parallel synthesis. J Med Chem 49: 656-663.
94. Polster BM, Basanez G, Young M, Suzuki M, Fiskum G, (2003). Inhibition of Bax-induced cytochrome c release from neural cell and brain mitochondria by dibucaine and propranolol. J Neurosci 23: 2735-2743.
95. Porter J, Payne A, De Candole B, Ford D, Hutchinson B, Trevitt G, et al. (2009a). Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selective Bcl-2 inhibitors. Bioorg Med Chem Lett 19: 230-233.
96. Porter J, Payne A, Whitcombe I, De Candole B, Ford D, Garlish R, et al. (2009b). Atropisomeric small molecule Bcl-2 ligands: determination of bioactive conformation. Bioorg Med Chem Lett 19: 1767-1772.
97. Ready N, Karaseva NA, Orlov SV, Luft AV, Popovych O, Holmlund JT, et al. (2011). Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer. J Thorac Oncol 6: 781-785.
98. Reed JC, (2002). Apoptosis-based therapies. Nat Rev Drug Discov 1: 111-121.
99. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. (2012). 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.
100. Rodrigues CM, Sola S, Sharpe JC, Moura JJ, Steer CJ, (2003). Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry 42: 3070-3080.
101. Rooswinkel RW, van de Kooij B, Verheij M, Borst J, (2012). 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: e366.
102. Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, et al. (2012). Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18: 3163-3169.
103. Saito M, Korsmeyer SJ, Schlesinger PH, (2000). BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2: 553-555.
104. Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, et al. (1997). Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275: 983-986.
105. Schellenberg B, Wang P, Keeble JA, Rodriguez-Enriquez R, Walker S, Owens TW, et al. (2013). Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell 49: 959-971.
106. Schimmer AD, O'Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, et al. (2008). A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res 14: 8295-8301.
107. Schroeder GM, Wei D, Banfi P, Cai Z-W, Lippy J, Menichincheri M, et al. (2012). Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists. Bioorg Med Chem Lett 22: 3951-3956.
108. Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ, (1991). bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67: 879-888.
109. Simonen M, Keller H, Heim J, (1997). The BH3 domain of Bax is sufficient for interaction of Bax with itself and with other family members and it is required for induction of apoptosis. Eur J Biochem 249: 85-91.
110. Skelton NJ, Chen YM, Dubree N, Quan C, Jackson DY, Cochran A, et al. (2001). Structure-function analysis of a phage display-derived peptide that binds to insulin-like growth factor binding protein 1. Biochemistry 40: 8487-8498.
111. Sleebs BE, Czabotar PE, Fairbrother WJ, Fairlie WD, Flygare JA, Huang DC, et al. (2011). 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.
112. Sleebs BE, Kersten WJ, Kulasegaram S, Nikolakopoulos G, Hatzis E, Moss RM, et al. (2013). Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL. J Med Chem 56: 5514-5540.
113. Smith BJ, Lee EF, Checco JW, Evangelista M, Gellman SH, Fairlie WD, (2013). Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. ChemBioChem 14: 1564-1572.
114. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. (2013). ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19: 202-208.
115. Stewart ML, Fire E, Keating AE, Walensky LD, (2010). The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat Chem Biol 6: 595-601.
116. Suzuki M, Youle RJ, Tjandra N, (2000). Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 103: 645-654.
117. Toure BB, Miller-Moslin K, Yusuff N, Perez L, Dore M, Joud C, et al. (2013). The role of the acidity of N-heteroaryl sulfonamides as inhibitors of Bcl-2 family protein-protein interactions. ACS Med Chem Lett 4: 186-190.
118. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. (2008). ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68: 3421-3428.
119. Vaillant F, Mérino D, Lee L, Breslin K, Pal B, Ritchie ME, et al. (2013). Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 24: 120-129.
120. Vandenberg CJ, Cory S, (2013). ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood 121: 2285-2288.
121. Varadarajan S, Vogler M, Butterworth M, Dinsdale D, Walensky LD, Cohen GM, (2013). Evaluation and critical assessment of putative MCL-1 inhibitors. Cell Death Differ 20: 1475-1484.
122. Vaux DL, Cory S, Adams JM, (1988). Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335: 440-442.
123. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, et al. (2004). Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305: 1466-1470.
124. Walensky LD, Pitter K, Morash J, Oh KJ, Barbuto S, Fisher J, et al. (2006). A stapled BID BH3 helix directly binds and activates BAX. Mol Cell 24: 199-210.
125. Wang K, Gross A, Waksman G, Korsmeyer SJ, (1998). Mutagenesis of the BH3 domain of BAX identifies residues critical for dimerization and killing. Mol Cell Biol 18: 6083-6089.
126. Wei J, Kitada S, Rega M, Stebbins J, Zhai D, Cellitti J, et al. (2009a). Apogossypol derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem 52: 4511-4523.
127. Wei J, Kitada S, Rega MF, Emdadi A, Yuan HB, Cellitti J, et al. (2009b). Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins. Mol Cancer Ther 8: 904-913.
128. Wei J, Stebbins JL, Kitada S, Dash R, Placzek W, Rega MF, et al. (2010). BI-97C1, an optically pure apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem 53: 8000-8011.
129. Wells JA, McClendon CL, (2007). Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450: 1001-1009.
130. Westphal D, Dewson G, Czabotar PE, Kluck RM, (2011). Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta 1813: 521-531.
131. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, et al. (2005). Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19: 1294-1305.
132. Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, et al. (2007). Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315: 856-859.
133. Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, et al. (2010). 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.
134. Yang B, Liu D, Huang Z, (2004). Synthesis and helical structure of lactam bridged BH3 peptides derived from pro-apoptotic Bcl-2 family proteins. Bioorg Med Chem Lett 14: 1403-1406.
135. Youle RJ, Strasser A, (2008). The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9: 47-59.
136. Zha H, Aime-Sempe C, Sato T, Reed JC, (1996). Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J Biol Chem 271: 7440-7444.
137. Zhai D, Jin C, Satterthwait AC, Reed JC, (2006). Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ 13: 1419-1421.
138. Zhang H, Nimmer PM, Tahir SK, Chen J, Fryer RM, Hahn KR, et al. (2007). Bcl-2 family proteins are essential for platelet survival. Cell Death Differ 14: 943-951.
139. Zhang Z, Zhu W, Lapolla SM, Miao Y, Shao Y, Falcone M, et al. (2010). Bax forms an oligomer via separate, yet interdependent, surfaces. J Biol Chem 285: 17614-17627.
140. Zhou H, Aguilar A, Chen J, Bai L, Liu L, Meagher JL, et al. (2012a). Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity. J Med Chem 55: 6149-6161.
141. Zhou H, Chen J, Meagher JL, Yang C-Y, Aguilar A, Liu L, et al. (2012b). Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold. J Med Chem 55: 4664-4682.
142. Zhou L, Chang DC, (2008). Dynamics and structure of the Bax-Bak complex responsible for releasing mitochondrial proteins during apoptosis. J Cell Sci 121: 2186-2196.