吡唑酮衍生物作为强效和选择性的小分子 SIRT5 抑制剂。
Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors.
机构信息
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.
The First Affiliated Hospital of Dali University, Dali, 671000, PR China.
出版信息
Eur J Med Chem. 2023 Feb 5;247:115024. doi: 10.1016/j.ejmech.2022.115024. Epub 2022 Dec 16.
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 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.
Sirtiun 5（SIRT5）是一种依赖 NAD 的蛋白赖氨酸脱酰酶。它正成为治疗癌症和代谢相关疾病药物开发的有希望的靶点。在这项研究中，我们筛选了 5000 种化合物，并确定了一种含有吡唑啉酮官能团的命中化合物 14，它是一种新型的 SIRT5 选择性抑制剂。基于结构的优化得到了化合物 47，其 IC 值为 0.21±0.02 μM，效力提高了 100 倍。化合物 47 对 SIRT5 的选择性明显高于 SIRT1-3 和 SIRT6。生化研究表明，47 不占据 NAD 结合口袋，而是作为一种底物竞争性抑制剂。所鉴定的强效和选择性 SIRT5 抑制剂可作为研究工具和治疗剂进一步研究。
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