Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors

Jian Yao; Yudong Yin; Hong Han; Shaoting Chen; Yuxiang Zheng; Benji Liang; Mengyue Wu; Kangqi Shu; Bikash Debnath; David B Lombard; Quande Wang; Keguang Cheng; Nouri Neamati; Yanghan Liu

doi:10.1016/j.ejmech.2022.115024

Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors

Eur J Med Chem. 2023 Feb 5:247:115024. doi: 10.1016/j.ejmech.2022.115024. Epub 2022 Dec 16.

Authors

Jian Yao¹, Yudong Yin¹, Hong Han², Shaoting Chen¹, Yuxiang Zheng¹, Benji Liang¹, Mengyue Wu¹, Kangqi Shu¹, Bikash Debnath³, David B Lombard⁴, Quande Wang¹, Keguang Cheng⁵, Nouri Neamati⁶, Yanghan Liu⁷

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: kgcheng2008@gmail.com.
⁶ Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States. Electronic address: neamati@umich.edu.
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: lyh4291006@163.com.

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.

MeSH terms

Humans
Lysine
NAD / chemistry
NAD / metabolism
Neoplasms*
Pyrazolones* / pharmacology
Sirtuins* / metabolism

Substances

Sirtuins
NAD
Lysine
Pyrazolones
SIRT5 protein, human
SIRT6 protein, human

Grants and funding

R01 GM101171/GM/NIGMS NIH HHS/United States