Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives

作者：Chen, Hao; Wu, Guozhen; Gao, Shuang; Guo, Ruihua; Zhao, Zeng; Yuan, Hu; Liu, Shanxiang; Wu, Jian; Lu, Xiaolong; Yuan, Xing; Yu, Zongmin; Zu, Xianpeng; Xie, Ning; Yang, Niao; Hu, Zhenlin^*; Sun, Qingyan^*; Zhang, Weidong^*

来源：Journal of Medicinal Chemistry, 2017, 60(16): 6828-6852.

DOI：10.1021/acs.jmedchem.6b01829

• NF-KAPPA-B
• TUMOR-NECROSIS-FACTOR
• RHEUMATOID-ARTHRITIS
• SESQUITERPENE LACTONES
• PROLIFERATION
• INFLAMMATION
• LEUCETTAMOL
• CYTOKINES
• SURVIVAL
• ANTIBODY

As a therapeutic target for antitumor necrosis factor (TNF)-alpha interventions, UbcH5c is one of the key ubiquitin-conjugating enzymes catalyzing ubiquitination during TNF-alpha-triggered nuclear factor kappa B (NF-kappa B) activation. In the present study, three series of analogues were designed and synthesized from alpha-santonin, and their UbcH5c inhibitory activities were screened by Western blotting and NF-kappa B luciferase assay. Further BIAcore, in-gel fluorescence imaging, and immunoprecipitation assays demonstrated that compound 6d exhibited robust and specific inhibition of UbcH5c, exceeding that of the positive compound 1 (IJ-5). Mechanistic investigations revealed that compound 6d preferentially bound to and inactivated UbcH5c by forming a covalent adduct with its active site Cys85. Furthermore, compound 6d exhibited potent anti-inflammatory activity against complete Freunds adjuvant-induced adjuvant arthritis in vivo. These findings suggest that the novel alpha-santonin-derived UbcH5c inhibitor 6d is a promising lead compound for the development of new antirheumatoid arthritis (RA) agent.

• 出版日期2017-8-24
• 单位中国人民解放军第二军医大学; 上海中医药大学; 上海医药工业研究院