Bcl-2, Bcl-xL, and MCL-1 (Bcl-2, Bcl-xL, MCL-1)

B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), and Myeloid cell leukemia 1 (MCL-1) are anti-apoptotic proteins in the Bcl-2 family that maintain mitochondrial integrity by inhibiting activation of pro-apoptotic proteins such as BAX and BAK. They function by sequestering pro-apoptotic BH3-only proteins (e.g., BIM), blocking the apoptotic cascade. All three are widely overexpressed in cancer and are associated with resistance to cell death and to targeted therapies, making them prominent therapeutic targets. Drug development has focused on selective and combinatorial BH3-mimetics that antagonize these proteins' survival functions. However, therapeutic challenges include tissue toxicity and acquired resistance driven by compensatory protein expression.

Other names

BCL2B-cell lymphoma 2BCL2L1B-cell lymphoma-extra largeMCL1myeloid cell leukemia sequence 1MCL-1LMCL-1S

BH3-mimetics block anti-apoptotic Bcl-2 family proteins by binding to their BH3-binding groove, displacing pro-apoptotic proteins (e.g., BIM), resulting in activation of BAX/BAK and induction of apoptosis. Indirect actions by destabilizing the balance of pro- and anti-apoptotic proteins at the mitochondria