Anti-apoptotic B-cell lymphoma 2 family proteins (MCL-1, BCL-2, BCL-xL, BCL-w) (MCL-1/BCL-2/BCL-xL/BCL-w)

The target group comprises the primary anti-apoptotic members of the B-cell lymphoma 2 (BCL-2) family: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL-1), Apoptosis regulator Bcl-2 (BCL-2), Bcl-2-like protein 1 (BCL-xL), and Bcl-2-like protein 2 (BCL-w). These proteins are essential for maintaining cell survival by sequestering pro-apoptotic 'BH3-only' proteins and preventing the activation of BAX and BAK, thereby preserving mitochondrial outer membrane integrity. In many malignancies, one or more of these proteins are overexpressed, providing a survival advantage to cancer cells and contributing to resistance against conventional chemotherapy and targeted treatments. Therapeutic intervention focuses on the use of BH3 mimetics, which competitively bind to the hydrophobic grooves of these pro-survival proteins to trigger apoptosis. While selective inhibitors like venetoclax (targeting BCL-2) have revolutionized the treatment of certain hematological cancers, multi-target or 'pan' inhibitors are developed to overcome resistance caused by the compensatory upregulation of other family members. However, broad inhibition presents significant clinical challenges, most notably BCL-xL-mediated thrombocytopenia and potential systemic toxicities related to the physiological roles of these proteins in healthy tissues such as the heart and hematopoietic system.

Other names

Pro-survival BCL-2 family proteinsAnti-apoptotic BCL-2 membersB-cell lymphoma 2 familyMCL1/BCL2/BCL2L1/BCL2L2

These targets are inhibited by BH3 mimetics, which are small molecules that bind to the hydrophobic BH3-binding groove of anti-apoptotic proteins. This binding displaces pro-apoptotic BH3-only proteins (such as BIM, PUMA, and NOXA) or effector proteins (BAX and BAK), leading to mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and the activation of the caspase cascade, ultimately resulting in programmed cell death (apoptosis).