title: The discovery of a novel inhibitor of apoptotic protease activating factor-1 (Apaf-1) for ischemic heart: synthesis, activity and target identification.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Nantong University, Nantong, 226001, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.|School of Pharmacy, Macao University of Science and Technology, Macao.
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000737:chemistry / Q000378:metabolism; D053453:Caspase 9 / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D062105:Molecular Docking Simulation; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats
chemical_list: C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D002316:Cardiotonic Agents; D053148:Caspase 3; D053453:Caspase 9