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Apaf-1 is a central component in the apoptosis regulatory network for the treatment of apoptosis related diseases. Excessive Apaf-1 activity induced by myocardial ischemia causes cell injury. No drug targeted to Apaf-1 for treating myocardial ischemia has been reported to the best of our knowledge. In the present work, we synthesized a novel compound,  ZYZ-488 , which exhibited significant cardioprotective property in significantly increasing the viability of hypoxia-induced H9c2 cardiomyocytes and reducing CK and LDH leakage. Further study suggested the protective activity of  ZYZ-488  dependent on its anti-apoptosis effect. This anti-apoptotic effect is most probably related to its disturbing the interaction between Apaf-1 and procaspase-9 as the target fishing and molecular docking indicated. The suppression on the activation of procaspase-9 and procaspase-3 with  ZYZ-488  strongly suggested that compound  ZYZ-488  could be a novel inhibitor of Apaf-1. In conclusion,  ZYZ-488  as a novel small molecule competitive inhibitor of Apaf-1, with the great potential for treating cardiac ischemia.

scientific reports

The discovery of a novel inhibitor of apoptotic protease activating factor-1 (Apaf-1) for ischemic heart: synthesis, activity and target identification