Cancer cell death strategies by targeting Bcl-2's BH4 domain

The Bcl-2-family proteins have long been known for their role as key regulators of apoptosis. Overexpression various members the family is associated with oncogenesis. Its founding member, anti-apoptotic Bcl-2 regulates cell death at different levels, whereby emerged a major drug target to eradicate cancers through death. This resulted in development venetoclax, antagonist that acts BH3 mimetic. Venetoclax already entered clinic treat relapse chronic lymphocytic leukemia patients. Here, we discuss decision-maker focus on recent advances anti-cancer therapeutics BH4 domain Bcl-2, thereby interfering non-canonical functions Ca2+-signaling modulation. In particular, critically previously developed tools, including peptide BIRD-2 (Bcl-2/IP3R-disrupter-2) and small molecule BDA-366. addition, present preliminary analysis two recently identified molecules from molecular modeling approach Bcl-2's domain, which however failed induce Bcl-2-dependent diffuse large B-cell lymphoma models. Overall, antagonizing by its BH4-domain biology holds promise elicit cancer, though improved tools on-target remain necessary ought be designed.