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J Med Chem. 2017 Aug 24;60(16):6828-6852. doi: 10.1021/acs.jmedchem.6b01829. Epub 2017 Aug 2.

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

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School of Pharmacy, Second Military Medical University , Shanghai 200433, China.
Shanghai Institute of Pharmaceutical Industry , Shanghai 200040, China.
Progenra, Inc. , 277 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
Lifesensors, Inc. , 271 Great Valley Parkway, Malvern, Pennsylvania 19355, United States.
State Key Laboratory of Innovative Natural Medicine and TCM Injections, Jiangxi Qingfeng Pharmaceutical Co., Ltd. , Ganzhou 341000, Jiangxi, China.
Institute of Interdisciplinary Research Complex, Shanghai University of Traditional Chinese Medicine , Shanghai 201210, China.


As a therapeutic target for antitumor necrosis factor (TNF)-α interventions, UbcH5c is one of the key ubiquitin-conjugating enzymes catalyzing ubiquitination during TNF-α-triggered nuclear factor kappa B (NF-κB) activation. In the present study, three series of analogues were designed and synthesized from α-santonin, and their UbcH5c inhibitory activities were screened by Western blotting and NF-κB 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 Freund's adjuvant-induced adjuvant arthritis in vivo. These findings suggest that the novel α-santonin-derived UbcH5c inhibitor 6d is a promising lead compound for the development of new antirheumatoid arthritis (RA) agent.

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