B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-XL) (Bcl-2/Bcl-XL)

B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-XL) are integral membrane proteins that act as potent inhibitors of programmed cell death, or apoptosis (UniProt P10415, Q07817). They function by binding and neutralizing pro-apoptotic members of the Bcl-2 family, such as BAX and BAK, thereby preventing mitochondrial outer membrane permeabilization and the subsequent release of cytochrome c (PubMed: 31535024). Overexpression of these proteins is a hallmark of various malignancies, including chronic lymphocytic leukemia and several solid tumors, where they contribute to tumor cell survival and therapeutic resistance (NCI). Drugs known as BH3 mimetics, such as venetoclax and navitoclax, have been developed to target these proteins by mimicking the action of endogenous pro-apoptotic BH3-only proteins (PubChem CID 49819184). While targeting Bcl-2 has proven highly effective in treating certain blood cancers, the inhibition of Bcl-XL is associated with a rapid decline in platelet counts, presenting a significant clinical challenge for dual-targeting agents (PubMed: 23428990). Additionally, these proteins are being investigated as targets for senolytic therapies due to their role in the survival of senescent cells (PubMed: 26711331).

Other names

BCL2BCL2L1Apoptosis regulator Bcl-2B-cell lymphoma-extra largeBcl-xLBcl-2-like protein 1Bcl2-L-1

BH3 mimetics that bind to the hydrophobic groove of anti-apoptotic Bcl-2 family proteins, displacing pro-apoptotic BH3-only proteins (like BIM) or directly preventing BAX/BAK activation, thereby triggering mitochondrial outer membrane permeabilization and subsequent apoptosis (PubMed: 31535024).