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

The B-cell lymphoma 2 (Bcl-2) related apoptotic pathway is a critical regulatory network that controls the intrinsic (mitochondrial) pathway of programmed cell death (Citation: PubMed 28101115). This pathway is defined by the interactions between three groups of Bcl-2 family proteins: anti-apoptotic members (e.g., Bcl-2, Bcl-xL, Mcl-1), pro-apoptotic effectors (e.g., Bax, Bak), and pro-apoptotic BH3-only initiators (e.g., Bim, Bid, Bad) (Citation: UniProt P10415). In many cancers, particularly hematologic malignancies like chronic lymphocytic leukemia (CLL), the overexpression of anti-apoptotic proteins allows malignant cells to survive despite oncogenic stress or DNA damage (Citation: NIH/NCI). Therapeutic targeting of this pathway primarily utilizes BH3 mimetics, which are small molecules designed to occupy the hydrophobic binding groove of anti-apoptotic proteins, thereby releasing pro-apoptotic factors to trigger mitochondrial outer membrane permeabilization (MOMP) and subsequent apoptosis (Citation: PubMed 31034570). Venetoclax is the first-in-class selective Bcl-2 inhibitor approved for clinical use, demonstrating significant efficacy in CLL and acute myeloid leukemia (AML). However, the use of these agents is associated with risks such as tumor lysis syndrome (TLS) due to rapid cell death and hematologic toxicities like neutropenia (Citation: StatPearls).

Other names

Bcl-2 family proteinsBcl-2 related apoptotic pathwayIntrinsic apoptotic pathway regulatorsB-cell lymphoma 2 family

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