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

The B-cell lymphoma 2 (Bcl-2) family of proteins consists of evolutionarily conserved regulators that govern the intrinsic (mitochondrial) pathway of apoptosis [1, 2]. These proteins are categorized into three functional groups: anti-apoptotic members (e.g., Bcl-2, Bcl-xL, Mcl-1) that promote cell survival, pro-apoptotic effectors (e.g., Bax, Bak) that permeabilize the mitochondrial membrane, and pro-apoptotic BH3-only proteins (e.g., Bim, Puma, Bad) that act as stress sensors [1, 4]. The balance between these groups determines whether a cell lives or undergoes programmed cell death by controlling mitochondrial outer membrane permeabilization (MOMP) and the subsequent release of cytochrome c [2, 15]. In many cancers, anti-apoptotic Bcl-2 family members are overexpressed, allowing malignant cells to evade apoptosis and develop resistance to chemotherapy [5, 12]. This has made the family a primary target for drug development, leading to the creation of "BH3 mimetics" like venetoclax [13, 14]. These small molecules bind to the hydrophobic grooves of anti-apoptotic proteins, releasing pro-apoptotic factors to trigger cell death [14, 18]. While highly effective in hematologic malignancies, therapeutic challenges include managing on-target toxicities like thrombocytopenia and overcoming resistance mechanisms such as the compensatory upregulation of alternative family members like Mcl-1 [1, 10].

Other names

Bcl-2 family proteinsB-cell CLL/lymphoma 2 familyApoptosis regulator Bcl-2 familyBcl-2 family of cell death regulators

BH3 mimetics that bind to the hydrophobic groove of anti-apoptotic Bcl-2 family proteins, displacing pro-apoptotic members to induce mitochondrial outer membrane permeabilization and apoptosis.