European journal of medicinal chemistry · 2022
Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors.
СтатьяНазвание и аннотация: Перевод в очереди
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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, Liu Yanghan
Аннотация
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.