2. Academic Validation
  3. Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors

Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors

  • Eur J Med Chem. 2022 Dec 16;247:115024. doi: 10.1016/j.ejmech.2022.115024.
Jian Yao 1,  Yudong Yin 1,  Hong Han 2,  Shaoting Chen 1,  Yuxiang Zheng 1,  Benji Liang 1,  Mengyue Wu 1,  Kangqi Shu 1,  Bikash Debnath 3,  David B Lombard 4,  Quande Wang 1,  Keguang Cheng 5,  Nouri Neamati 6,  Yanghan Liu 7
Affiliations

Affiliations

  • 1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China.
  • 2 The First Affiliated Hospital of Dali University, Dali, 671000, PR China.
  • 3 Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States.
  • 4 Department of Pathology & Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, United States.
  • 5 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: [email protected].
  • 6 Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address: [email protected].
  • 7 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: [email protected].
PMID: 36543033 DOI: 10.1016/j.ejmech.2022.115024
Abstract

Sirtiun 5 (SIRT5) is a NAD+-dependent protein lysine deacylase. It is emerging as a promising target for the development of drugs to treat Cancer and metabolism-related diseases. In this study, we screened 5000 compounds and identified a hit compound 14 bearing a pyrazolone functional group as a novel SIRT5-selective inhibitor. Structure-based optimization of 14 resulted in compound 47 with an IC50 value of 0.21 ± 0.02 μM and a 100-fold improved potency. Compound 47 showed substantial selectivity for SIRT5 over SIRT1-3 and SIRT6. Biochemical studies suggest that 47 does not occupy the NAD + -binding pocket and acts as a substrate-competitive inhibitor. The identified potent and selective SIRT5 inhibitors allow further studies as research tools and therapeutic agents.

Keywords

Deacetylase; Molecular docking; SIRT5 inhibitors; Sirtuins; Structure-activity relationship.

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