Dose-limiting toxicity to healthy tissues is among the major hurdles in anticancer treatment along with intrinsic or acquired
multi-drug resistance. Development of small molecule inhibitors (SMI) specific for antiapoptotic Bcl-2 proteins is a novel approach in a
way that these antagonists are aimed to interfere with specific protein-protein interactions unlike conventional chemo-/radiotherapies.
SMIs of antiapoptotic Bcl-2 proteins are assumed to compete with proapoptotic Bcl-2s to occupy BH3 docking grooves on the surfaces of
antiapoptotic family members. Instead of directly initiating cell death, these inhibitors are intended to decrease apoptotic threshold in
tumor cells that were already primed to death. In this regard, antiapoptotic Bcl-2 protein SMIs have the advantage of lower normal tissue
toxicity relative to conventional anticancer therapies that interfere with general mechanisms including DNA synthesis, mitosis and
tyrosine kinase activity. Besides, Bcl-2 antagonists were shown to potentiate efficacies of established drugs in several hematological
malignancies and solid tumors which render them promising candidates for combination anticancer therapy. Utilizing these SMIs in such
a way may prove to decrease the patient drug load by diminishing the required chemo-/radiotherapy dose. This review summarizes and
compares BH3 mimetics on the basis of specificity, mode of action and efficacy, as well as providing remarks on their therapeutical
potential and routes of development in near future.
Keywords: ABT-737, anticancer, apoptosis, Bcl-2, BH3 mimetic, cancer, gossypol, small molecule inhibitor, obatoclax
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