B-cell lymphoma 2 family anti-apoptotic protein (Bcl-2 family)

The B-cell lymphoma 2 (Bcl-2) family of anti-apoptotic proteins, which includes Bcl-2, Bcl-xL, Mcl-1, Bcl-w, and Bfl-1/A1, serves as the primary gatekeeper of the intrinsic (mitochondrial) apoptotic pathway [1.1.2, 1.4.3]. These proteins function by binding and sequestering pro-apoptotic members of the same family, such as the effectors BAX and BAK or the BH3-only initiators like BIM and PUMA, thereby preventing mitochondrial outer membrane permeabilization (MOMP) and the subsequent release of cytochrome c [1.1.1, 1.3.4]. In many malignancies, particularly hematological cancers like chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), these anti-apoptotic proteins are overexpressed, allowing tumor cells to evade programmed cell death and resist chemotherapy [1.1.3, 1.2.2]. Therapeutic targeting of this family has led to the development of BH3 mimetics, small molecules that occupy the hydrophobic binding groove of anti-apoptotic proteins to displace pro-apoptotic factors and trigger apoptosis [1.3.1, 1.4.1]. Venetoclax is the first FDA-approved selective Bcl-2 inhibitor, while other agents targeting Bcl-xL or Mcl-1 are currently under clinical investigation [1.3.1, 1.3.3]. Clinical use of these inhibitors requires careful management of safety concerns such as tumor lysis syndrome and cytopenias [1.3.3].

Other names

Bcl-2 family anti-apoptotic proteinsPro-survival Bcl-2 family proteinsAnti-apoptotic Bcl-2 family membersBcl-2 family

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