Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors.

Authors :: Yao J
Yin Y
Han H
Chen S
Zheng Y
Liang B
Wu M
Shu K
Debnath B
Lombard DB
Wang Q
Cheng K
Neamati N
Liu Y
Source :: European journal of medicinal chemistry [Eur J Med Chem] 2023 Feb 05; Vol. 247, pp. 115024. Date of Electronic Publication: 2022 Dec 16.
Publication Year :: 2023
Abstract: Sirtiun 5 (SIRT5) is a NAD <superscript>+</superscript> -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 <subscript>50</subscript> 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  <superscript>+</superscript>  -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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)