B‐cell lymphoma‐2 family proteins in the crosshairs: Small molecule inhibitors and activators for cancer therapy

Abstract The B‐cell lymphoma‐2 (BCL‐2) family of proteins plays a crucial role in the regulation of apoptosis, offering a dual mechanism for its control. Numerous studies have established a strong association between gene disorders of these proteins and the proliferation of diverse cancer cell types. Consequently, the identification and development of drugs targeting BCL‐2 family proteins have emerged as a prominent area in antitumor therapy. Over the last two decades, several small‐molecules have been designed to modulate the protein–protein interactions between anti‐ and proapoptotic BCL‐2 proteins, effectively suppressing tumor growth and metastasis in vivo. The primary focus of research has been on developing BCL‐2 homology 3 (BH3) mimetics to target antiapoptotic BCL‐2 proteins, thereby competitively releasing proapoptotic BCL‐2 proteins and restoring the blocked intrinsic apoptotic program. Additionally, for proapoptotic BCL‐2 proteins, exogenous small molecules have been explored to activate cell apoptosis by directly interacting with executioner proteins such as BCL‐2‐associated X protein (BAX) or BCL‐2 homologous antagonist/killer protein (BAK). In this comprehensive review, we summarize the inhibitors and activators (sensitizers) of BCL‐2 family proteins developed over the past decades, highlighting their discovery, optimization, preclinical and clinical status, and providing an overall landscape of drug development targeting these proteins for therapeutic purposes.