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

The B-cell lymphoma 2 (BCL-2) anti-apoptotic protein family, including BCL-2, BCL-XL, BCL-W, MCL-1, and BFL-1/A1, are critical regulators of the intrinsic apoptotic pathway (Source: UniProt: P10415). These proteins function by sequestering pro-apoptotic BH3-only proteins and neutralizing the pore-forming proteins BAX and BAK, thereby maintaining mitochondrial outer membrane integrity and preventing cell death (Source: PubMed: 29973712). In many cancers, these anti-apoptotic proteins are overexpressed, allowing malignant cells to evade apoptosis and develop resistance to chemotherapy (Source: PubMed: 32817543). Therapeutic strategies targeting this family primarily involve BH3 mimetics, which are small molecules designed to occupy the hydrophobic binding groove of the anti-apoptotic proteins. By displacing pro-apoptotic factors, these drugs trigger the activation of BAX/BAK and lead to rapid programmed cell death. Venetoclax, a selective BCL-2 inhibitor, has demonstrated significant clinical success in treating chronic lymphocytic leukemia and acute myeloid leukemia (Source: FDA Label). However, challenges such as resistance mediated by MCL-1 upregulation and toxicities like thrombocytopenia (associated with BCL-XL inhibition) remain key considerations in drug development (Source: PubMed: 28432230).

Other names

Anti-apoptotic BCL-2 proteinsPro-survival BCL-2 familyBCL2-like proteins

BH3 mimetics that bind to the hydrophobic groove of anti-apoptotic BCL-2 proteins, displacing pro-apoptotic BH3-only proteins and inducing mitochondrial outer membrane permeabilization (MOMP) and subsequent apoptosis (Source: PubMed: 31534203).