The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy

The B-cell lymphoma 2 (BCL2) protein family plays a central role in regulating apoptosis by controlling the mitochondrial release of cytochrome c. This comprehensive and forward-looking review outlines the fundamental biology of the BCL2 family, encompassing both canonical and non-canonical functions, and traces key milestones from foundational research to clinical applications in cancer and other pathological conditions.

We discuss the development and therapeutic potential of BH3-mimetics—small molecules that mimic pro-apoptotic BH3-only proteins—as well as emerging strategies such as proteolysis-targeting chimeras (PROTACs), antibody-drug conjugates (ADCs), and agents that target the BH4 domain of BCL2. Venetoclax, the first BCL2-selective BH3-mimetic, demonstrated significant clinical efficacy with an acceptable safety profile and has revolutionized the treatment landscape for several hematologic malignancies. Building on its success, other structurally related BCL2 inhibitors—such as sonrotoclax and lisaftoclax—are currently undergoing clinical evaluation, both as monotherapies and in combination regimens.

Genomic analyses underscore the critical roles of other anti-apoptotic family members, particularly BCL-XL and MCL1, across various cancer types, suggesting additional therapeutic opportunities for BH3-mimetics targeting these proteins. However, the clinical development of agents targeting BCL-XL and MCL1 has been hindered by dose-limiting, on-target toxicities—thrombocytopenia in the case of BCL-XL inhibition and cardiac toxicity for MCL1 inhibitors.

To overcome these challenges, innovative approaches such as PROTAC-mediated degradation and selective drug delivery systems are being explored to achieve tumor-specific targeting of BCL-XL or MCL1. These strategies have the potential to dramatically enhance therapeutic efficacy while minimizing systemic toxicity, particularly in malignancies highly dependent on these proteins for survival.

In summary, while targeting BCL2 family proteins has already marked a major success in translational oncology, ongoing advances in molecular design and delivery strategies may significantly broaden the clinical utility of this approach and improve outcomes across a wide range of diseases.