B-cell lymphoma 2 apoptosis regulator protein (Bcl-2) (Bcl-2)

B-cell lymphoma 2 (Bcl-2) is a pivotal anti-apoptotic protein that serves as a key regulator of the intrinsic apoptotic pathway (UniProt P10415). Located primarily on the outer mitochondrial membrane, Bcl-2 functions by sequestering pro-apoptotic BH3-only proteins, thereby preventing the activation and oligomerization of BAX and BAK, which would otherwise lead to mitochondrial outer membrane permeabilization (MOMP) and cell death (PubMed: 31535024). Overexpression of Bcl-2 is frequently observed in various malignancies, most notably B-cell lymphomas and leukemias, where it facilitates the survival of cancer cells and confers resistance to chemotherapy (StatPearls: NBK554581). This protein has become a major therapeutic target, leading to the development of BH3-mimetics such as venetoclax, which selectively bind to the hydrophobic groove of Bcl-2 to induce apoptosis in malignant cells (NIH: PMC6443613). Clinical use of Bcl-2 inhibitors has revolutionized the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, although challenges such as tumor lysis syndrome and acquired resistance mutations remain significant considerations (PubMed: 30610176).

Other names

BCL2B-cell CLL/lymphoma 2Apoptosis regulator Bcl-2B-cell lymphoma 2

Bcl-2 inhibitors, specifically BH3-mimetics, occupy the hydrophobic BH3-binding groove of the Bcl-2 protein. This competitive binding displaces pro-apoptotic proteins like BIM, allowing them to activate BAX and BAK, which leads to mitochondrial pore formation, cytochrome c release, and the initiation of the caspase cascade resulting in apoptosis (PubMed: 27135742).