The Bcl-2 proteins form a family of evolutionarily related proteins which are essential for maintaining the balance between cell death and cell proliferation, with different family members acting as either positive or negative modulators of apoptosis. The family is structurally subdivided into three distinct groups based on the presence of Bcl-2 homology (BH) domains (BH1-4).

1: Proapoptotic BH3-only subgroup; Bad, Bik, Bid, Bim, Hrk, Bmf, Noxa, Puma and bNIP3
2: Proapoptotic 'effectors'; Bak, Bok and Bax
3: Antiapoptotic subgroup; Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and Bcl2-A1.

Binding between pro- and anti-apoptotic members via BH domains dictates the death or survival of cells [3,9-10]. The BH3-only subgroup members initiate apoptosis in response to cellular damage. In response to these same signals the proapoptotic subgroup containing BH1-3 (Bax and Bak) oligomerize on the mitochondrial membrane, acting to increase mitochondrial membrane permeability to apoptogenic factors (such as cytochrome C) stored in the mitochondrial lumen. When released, these factors activate cell-killing caspases [7]. The antiapoptotic members contain all four BH domains and protect cells from apoptosis by directly binding to and sequestering their proapoptotic counterparts via BH3 interactions.

Overexpression of antiapoptotic Bcl-2 proteins is associated with various cancers in which the normal apoptotic pathway is inhibited, leading to abnormal and dysregulated cell proliferation [5]. Prosurvival Bcl-2 family proteins are therefore tractable drug targets for the development of novel anti-cancer therapies, as well as immunotherapies. Small molecule antagonists of the antiapoptotic Bcl-2 proteins would be expected to restore normal apoptotic signaling in tumor cells by up-regulating proapoptotic Bcl-2 protein activity. These compounds may also be able to combat the resistance to chemotherapy which often develops in Bcl-2-overexpressing cancers [1].

Synonyms and (human gene symbols);
Bcl-2 (BCL2), Bcl-xL (BCL2L1), Bcl-w (BCL2L2), Mcl-1 (MCL1), Bcl2-A1 (BCL2A1), Bax (BAX), Bok (BOK), Bak (BAK1), Bad (BAD), Bid (BID), Bim (BCL2L11), Bmf (BMF), Bik (BIK), Hrk (HRK), Noxa (PMAIP1), Puma (BBC3), bNIP3 (BNIP3).

1. Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC, Fornace Jr AJ. (2000) An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res, 60 (21): 6101-10. [PMID:11085534]

2. Boise LH, González-García M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nuñez G, Thompson CB. (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell, 74 (4): 597-608. [PMID:8358789]

3. Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J. (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol, 3 (2): 173-82. [PMID:11175750]

4. Doherty GA, Elmore SW, Hasvold LA, Souers AJ, Tao Z-F, Wang GT, Wang L, Mantei R, Hansen TM. (2013) Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases. Patent number: US8580794. Assignee: Abbvie Inc.. Priority date: 26/05/2009. Publication date: 12/11/2013.

5. Green DR, Evan GI. (2002) A matter of life and death. Cancer Cell, 1 (1): 19-30. [PMID:12086884]

6. Le Wang, George A. Doherty, Andrew S. Judd*, Zhi-Fu Tao, T. Matthew Hansen, Robin R. Frey, Xiaohong Song, Milan Bruncko, Aaron R. Kunzer, Xilu Wang, Michael D. Wendt, John A. Flygare, Nathaniel D. Catron, Russell A. Judge, Chang H. Park, Shashank Shekhar, Darren C. Phillips, Paul Nimmer, Morey L. Smith, Stephen K. Tahir, Yu Xiao, John Xue John Xue AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States More by John Xue , Haichao Zhang, Phuong N. Le, Michael J. Mitten, Erwin R. Boghaert, Wenqing Gao, Peter Kovar, Edna F. Choo, Dolores Diaz, Wayne J. Fairbrother, Steven W. Elmore, Deepak Sampath, Joel D. Leverson, and Andrew James Souers. (2020) Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor. ACS Med Chem Lett, [Epub ahead of print]. DOI: 10.1021/acsmedchemlett.9b00568

7. Shi Y. (2002) Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell, 9 (3): 459-70. [PMID:11931755]

8. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ et al.. (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med, 19 (2): 202-8. [PMID:23291630]

9. van Delft MF, Huang DC. (2006) How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res, 16 (2): 203-13. [PMID:16474435]

10. Youle RJ, Strasser A. (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 9 (1): 47-59. [PMID:18097445]