Abstract

The BCL2 family of proteins serves as a central regulator of mitochondrial outer membrane permeabilization (MOMP) and intrinsic apoptosis, with anti-apoptotic members such as BCL2, BCL-XL, and MCL1 frequently overexpressed in cancers to evade programmed cell death. Traditional BH3 mimetics, like venetoclax and navitoclax, have revolutionized treatment for hematologic malignancies by competitively inhibiting these pro-survival proteins, yet they face challenges including acquired resistance, on-target toxicities and limited efficacy in solid tumors due to reversible binding and incomplete target engagement. To address these limitations, covalent BH3 mimetics—such as NA1-115-7 and drimane derivatives—emerge as irreversible inhibitors that enhance potency and duration of action, particularly against MCL1 and BCL-XL, by forming stable adducts at key residues like histidine or cysteine. Complementing this, proteolysis-targeting chimeras (PROTACs), exemplified by DT2216 (BCL-XL-specific) and 753B (dual BCL-XL/BCL2 degrader), leverage the ubiquitin-proteasome system for catalytic degradation, offering superior selectivity and reduced dosing frequency while mitigating platelet toxicity through E3 ligase choice. These strategies enable precision apoptosis induction by exploiting tumor-specific dependencies, biomarker-guided patient stratification and synergistic combinations with chemotherapies or immunotherapies. Preclinical data demonstrate enhanced tumor clearance in leukemia and solid tumor models, with clinical trials underway. Despite hurdles like PROTAC pharmacokinetics and covalent off-target reactivity, these innovations promise to expand BCL2-targeted therapies beyond hematologic cancers, fostering a new era of targeted apoptosis modulation in oncology. This Mini review synthesizes recent advances in targeting BH3 Mimetics accompanied by PROTAC for activating apoptosis in cancer cells. Furthermore, this explores the challenges in application of BH3 Mimetics in inducing apoptosis.