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Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy

文献类型：期刊论文

作者Cheng, Yong -Jun1,2,4; Zhuang, Zhen2,3; Miao, Yu -Ling2,4; Song, Shan -Shan2,4; Bao, Xu-Bin2,4; Yang, Chun-Hao2,3; He, Jin-Xue1,2,4
刊名BIOCHEMICAL PHARMACOLOGY
出版日期2024-04-01
卷号222页码:11
关键词YCH2823 USP7 inhibitor FT671 BCL6 mTOR inhibitor
ISSN号0006-2952
DOI10.1016/j.bcp.2024.116071
通讯作者Yang, Chun-Hao(chyang@simm.ac.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要Inhibition of the human ubiquitin-specific protease 7 (USP7), the key deubiquitylating enzyme in regulating p53 protein levels, has been considered an attractive anticancer strategy. In order to enhance the cellular activity of FT671, scaffold hopping strategy was employed. This endeavor resulted in the discovery of YCH2823, a novel and potent USP7 inhibitor.YCH2823 demonstrated remarkable efficacy in inhibiting the growth of a specific subset of TP53 wild-type, -mutant, and MYCN-amplified cell lines, surpassing the potency of FT671 by approximately 5-fold. The mechanism of action of YCH2823 involves direct interaction with the catalytic domain of USP7, thereby impeding the cleavage of ubiquitinated substrates. An increase in the expression of p53 and p21, accompanied by G1 phase arrest and apoptosis, was observed upon treatment with YCH2823. Subsequently, the knockdown of p53 or p21 in CHP-212 cells exhibited a substantial reduction in sensitivity to YCH2823, as evidenced by a considerable increase in IC50 values up to 690-fold. Furthermore, YCH2823 treatment specifically enhanced the transcriptional and protein levels of BCL6 in sensitive cells. Moreover, a synergistic effect between USP7 inhibitors and mTOR inhibitors was observed, suggesting the possibility of novel therapeutic strategies for cancer treatment. In conclusion, YCH2823 exhibits potential as an anticancer agent for the treatment of both TP53 wild-type and -mutant tumors.
WOS关键词P53 ; STABILITY ; DISCOVERY ; POTENT ; HAUSP ; BCL-6
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001197766900001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/310571]  
专题新药研究国家重点实验室
通讯作者Yang, Chun-Hao; He, Jin-Xue
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xian Lin Ave, Nanjing 210046, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Cheng, Yong -Jun,Zhuang, Zhen,Miao, Yu -Ling,et al. Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy[J]. BIOCHEMICAL PHARMACOLOGY,2024,222:11.
APA Cheng, Yong -Jun.,Zhuang, Zhen.,Miao, Yu -Ling.,Song, Shan -Shan.,Bao, Xu-Bin.,...&He, Jin-Xue.(2024).Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy.BIOCHEMICAL PHARMACOLOGY,222,11.
MLA Cheng, Yong -Jun,et al."Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy".BIOCHEMICAL PHARMACOLOGY 222(2024):11.

入库方式： OAI收割

来源：上海药物研究所

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