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

The anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins are essential regulators of the intrinsic apoptosis pathway, primarily functioning to maintain mitochondrial outer membrane integrity (Czabotar et al., 2014, Nature Reviews Molecular Cell Biology). Key members of this group include Bcl-2, Bcl-xL, Mcl-1, Bcl-w, and Bfl-1/A1, which act by sequestering pro-apoptotic proteins to prevent the release of cytochrome c into the cytosol (Montero & Letai, 2018, Nature Reviews Cancer). Overexpression of these proteins is a hallmark of many cancers, particularly hematologic malignancies, where they provide a survival advantage and confer resistance to chemotherapy (Adams & Cory, 2018, Cold Spring Harbor Perspectives in Biology). Therapeutic intervention focuses on BH3 mimetics, such as the FDA-approved Bcl-2 inhibitor Venetoclax, which competitively bind the hydrophobic groove of these proteins to trigger programmed cell death in malignant cells (FDA, 2016, Venclexta Label). While highly effective, targeting this family presents challenges such as dose-limiting toxicities like thrombocytopenia—linked to Bcl-xL's role in platelet survival—and the risk of rapid tumor debulking leading to tumor lysis syndrome (Roberts et al., 2016, New England Journal of Medicine).

Other names

Pro-survival Bcl-2 proteinsBcl-2-like proteinsB-cell CLL/lymphoma 2 familyAnti-apoptotic Bcl-2 members

These proteins function as targets for BH3 mimetics; drugs bind to the hydrophobic surface groove of anti-apoptotic Bcl-2 members, displacing pro-apoptotic BH3-only proteins (e.g., BIM, PUMA) and preventing the sequestration of BAX and BAK, thereby inducing mitochondrial outer membrane permeabilization (MOMP) and subsequent apoptosis (You et al., 2022, Nature Reviews Drug Discovery; Czabotar et al., 2014, Nature Reviews Molecular Cell Biology).