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

  • Sci Rep. 2016 Jul 22;6:29820. doi: 10.1038/srep29820.
Ying Wang  1 ,  Yang Cao  2 ,  Qing Zhu  3 ,  Xianfeng Gu  2 ,  Yi Zhun Zhu  1  4
Affiliations
  • 1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3. School of Pharmacy, Nantong University, Nantong, 226001, China.
  • 4. School of Pharmacy, Macao University of Science and Technology, Macao.
PMID: 27443636 DOI: 10.1038/srep29820
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.

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