论文｜Yan, Y.-H.; Wei, L.-L.; Wu, J.-W.; Wei, S.-Q.; Jiang, Y.-Y.; Yu, J.-L.; Yang, L.-L.; Li, G.-B: Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform

本文（Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform）原载Journal of Medicinal Chemistry，由四川大学李国菠教授等科研人员创作，系四川智慧社会智能治理重点实验室智慧法治研究所的系列学术成果。本网站后续将持续分享实验室的系列学术成果，欢迎大家阅读。

Abstract: COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, CFP-1, that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5. By using this platform, we identified 2-aminothiazole-4-carboxylic acids as new CSN5 inhibitors, which inhibited CSN5 but slightly downregulated PD-L1 in cancer cells. Furthermore, through the integration of deep learning-enabled virtual screening, we discovered that shikonins are nanomolar CSN5 inhibitors, which can upregulate PD-L1 in HCT116 cells. The binding modes of these structurally distinct inhibitors with CSN5 were explored by using microsecond-scale molecular dynamics simulations and tryptophan quenching assays.

Yan, Y.-H.; Wei, L.-L.; Wu, J.-W.; Wei, S.-Q.; Jiang, Y.-Y.; Yu, J.-L.; Yang, L.-L.; Li, G.-B. Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform. J. Med. Chem. 2024, 67, 14649-14667.   （论文下载）