B-cell lymphoma 2 family (Bcl-2 family) (Bcl-2 family)

The B-cell lymphoma 2 (Bcl-2) family consists of evolutionarily conserved proteins that serve as the primary regulators of the intrinsic (mitochondrial) pathway of apoptosis [1, 13, 23]. This family is structurally and functionally divided into three groups: anti-apoptotic proteins (e.g., BCL-2, BCL-XL, MCL-1), pro-apoptotic effector proteins (BAX and BAK), and pro-apoptotic BH3-only initiator proteins (e.g., BIM, PUMA, BAD) [5, 12, 15]. These members interact through their Bcl-2 homology (BH) domains to function as a molecular rheostat, governing the integrity of the mitochondrial outer membrane [13, 15, 20]. When pro-apoptotic signals prevail, BAX and BAK undergo oligomerization to cause mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c and subsequent cell death [7, 11, 20]. In many diseases, particularly cancer, the balance of the Bcl-2 family is disrupted through the overexpression of anti-apoptotic members or the loss of pro-apoptotic ones, allowing cells to evade programmed death and resist therapy [1, 4, 18, 21]. This biological dependence makes them high-priority therapeutic targets, leading to the development of BH3 mimetics such as venetoclax [1, 4, 10, 15]. These small-molecule drugs competitively bind to the hydrophobic grooves of anti-apoptotic proteins, displacing pro-apoptotic "activators" to trigger apoptosis specifically in malignant cells [7, 12, 14, 26]. Clinical application of these agents has significantly improved outcomes in hematological malignancies, though challenges like tumor lysis syndrome and acquired resistance through BCL2 mutations remain prominent [4, 8, 10, 24].

Other names

B-cell lymphoma 2 protein familyB-cell CLL/lymphoma 2 familyApoptosis regulator Bcl-2 familyBCL2 apoptosis regulatorsBH3-domain containing proteins

BH3 mimetics that competitively inhibit anti-apoptotic BCL-2 family members by binding to their hydrophobic grooves, thereby displacing pro-apoptotic proteins to trigger mitochondrial outer membrane permeabilization (MOMP) and subsequent apoptosis.