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Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors.
- 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.)
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 247
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36543033
- Full Text :
- https://doi.org/10.1016/j.ejmech.2022.115024