B-cell lymphoma 2 family anti-apoptotic protein (BCL-2 family) (BCL-2 family)

Anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins are essential regulators of the intrinsic (mitochondrial) pathway of apoptosis, acting as gatekeepers that prevent cell death by sequestering pro-apoptotic BH3-only proteins and neutralizing the pore-forming proteins BAX and BAK (PMID: 31611538). Key members of this group include BCL-2, BCL-XL, BCL-W, MCL-1, and BFL-1/A1. In many cancers, particularly hematologic malignancies like chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), these proteins are overexpressed, enabling cancer cells to survive under conditions that would normally trigger apoptosis, such as DNA damage or growth factor deprivation (PMID: 32814825). Therapeutic targeting of these proteins has been revolutionized by the development of BH3 mimetics, such as venetoclax, which bind to the hydrophobic groove of anti-apoptotic proteins to release pro-apoptotic factors and induce rapid cell death (PMID: 30135609). While highly effective, the use of these inhibitors can be limited by toxicities like tumor lysis syndrome and the development of resistance through the upregulation of alternative family members like MCL-1.

Other names

Pro-survival BCL-2 proteinsAnti-apoptotic BCL-2 family membersBCL-2-like proteins

BH3 mimetics bind to the hydrophobic surface groove of anti-apoptotic BCL-2 family proteins (e.g., BCL-2, BCL-XL, MCL-1), thereby displacing pro-apoptotic BH3-only proteins (like BIM, PUMA, or BID) or directly preventing the sequestration of BAX and BAK. This displacement allows BAX and BAK to oligomerize and form pores in the mitochondrial outer membrane, leading to the release of cytochrome c and subsequent activation of the caspase cascade, resulting in programmed cell death (PMID: 30135609, 31611538).