B-cell lymphoma 2 family (BCL2 family)

The B-cell lymphoma 2 (BCL2) family of proteins consists of critical regulators of the intrinsic apoptotic pathway, categorized into anti-apoptotic and pro-apoptotic members [2, 6, 14]. Anti-apoptotic proteins, such as BCL2 and BCL-XL, maintain cell survival by sequestering pro-apoptotic executioners like BAX and BAK [1, 4, 13]. In many cancers, the overexpression of these anti-apoptotic proteins allows malignant cells to evade programmed cell death, contributing to tumor progression and therapy resistance [2, 3, 10]. Therapeutic strategies targeting this family focus on BH3 mimetics, small molecules designed to occupy the hydrophobic binding grooves of anti-apoptotic proteins [3, 5, 6]. By displacing pro-apoptotic factors, these drugs trigger mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c and subsequent caspase activation [4, 7, 14]. Venetoclax, a selective BCL2 inhibitor, has shown significant clinical success in treating hematologic malignancies like chronic lymphocytic leukemia [2, 10, 11]. However, targeting other family members like BCL-XL can lead to side effects such as thrombocytopenia, as platelets are highly dependent on BCL-XL for survival [1, 3, 11]. Ongoing research aims to overcome resistance mechanisms, such as the upregulation of MCL-1, through combination therapies and the development of next-generation inhibitors [2, 3, 11].

Other names

BCL-2 familyB-cell CLL/lymphoma 2 familyBcl-2/Bcl-xL proteinsApoptosis regulators

BH3 mimetics that bind to the hydrophobic groove of anti-apoptotic BCL2 family proteins, displacing pro-apoptotic proteins to induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis.