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

The anti-apoptotic B-cell lymphoma 2 (Bcl-2) family consists of key regulatory proteins that inhibit the intrinsic (mitochondrial) pathway of apoptosis to promote cell survival [1.1.1, 1.2.1]. Members such as Bcl-2, Bcl-xL, and Mcl-1 contain four Bcl-2 homology (BH) domains and typically reside on the outer mitochondrial membrane, where they sequester pro-apoptotic proteins like BAX, BAK, and BH3-only activators [1.2.3, 1.2.5]. Overexpression of these proteins is a hallmark of many malignancies, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), allowing cancer cells to evade programmed cell death and resist chemotherapy [1.1.3, 1.3.1]. Therapeutic targeting of this family has been revolutionized by BH3 mimetics, such as the FDA-approved Bcl-2 inhibitor venetoclax, which bind to the hydrophobic groove of anti-apoptotic proteins to release pro-apoptotic factors [1.3.1, 1.4.5]. While highly effective in hematologic cancers, challenges include managing side effects like tumor lysis syndrome and thrombocytopenia, as well as overcoming resistance mediated by mutations or compensatory upregulation of other family members [1.4.2, 1.4.5]. Beyond apoptosis, these proteins also play roles in calcium signaling, mitochondrial bioenergetics, and autophagy [1.2.3, 1.2.4].

Other names

Pro-survival Bcl-2 familyBcl-2-like proteinsB-cell lymphoma 2 familyAnti-apoptotic Bcl-2 proteins

BH3 mimetics bind to the hydrophobic groove of anti-apoptotic Bcl-2 family proteins, displacing pro-apoptotic BH3-only proteins and effectors (BAX/BAK) to trigger mitochondrial outer membrane permeabilization and subsequent cell death [1.3.1, 1.3.3, 1.3.5].