1. Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors.
- Author
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Yao, Jian, Yin, Yudong, Han, Hong, Chen, Shaoting, Zheng, Yuxiang, Liang, Benji, Wu, Mengyue, Shu, Kangqi, Debnath, Bikash, Lombard, David B., Wang, Quande, Cheng, Keguang, Neamati, Nouri, and Liu, Yanghan
- Subjects
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MOLECULAR docking , *DRUG development , *FUNCTIONAL groups , *NAD (Coenzyme) , *PYRAZOLONES - 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 IC 50 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. [Display omitted] • Hit compound 14 bearing a pyrazolone skeleton was identified as a SIRT5 inhibitor. • Extensive SAR studies guided by molecular docking were conducted. • Compound 47 showed a 100-fold increased potency as compared to the original hit. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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