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Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform.
Yan, Yu-Hang; Wei, Liu-Liu; Wu, Jing-Wei; Wei, Si-Qi; Jiang, Ying-Ying; Yu, Jun-Lin; Yang, Ling-Ling; Li, Guo-Bo.
Afiliación
  • Yan YH; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • Wei LL; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • Wu JW; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • Wei SQ; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • Jiang YY; College of Food and Bioengineering, Xihua University, Chengdu 610039, China.
  • Yu JL; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • Yang LL; College of Food and Bioengineering, Xihua University, Chengdu 610039, China.
  • Li GB; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
J Med Chem ; 67(16): 14649-14667, 2024 Aug 22.
Article en En | MEDLINE | ID: mdl-39129245
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complejo del Señalosoma COP9 Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complejo del Señalosoma COP9 Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos