2. Academic Validation
  3. Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy

Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy

  • Biochem Pharmacol. 2024 Apr:222:116071. doi: 10.1016/j.bcp.2024.116071.
Yong-Jun Cheng 1,  Zhen Zhuang 2,  Yu-Ling Miao 3,  Shan-Shan Song 3,  Xu-Bin Bao 3,  Chun-Hao Yang 4,  Jin-Xue He 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Avenue, Nanjing 210046 China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 3 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China. Electronic address: chyang@simm.ac.cn.
  • 5 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Avenue, Nanjing 210046 China. Electronic address: jinxue_he@simm.ac.cn.
PMID: 38387527 DOI: 10.1016/j.bcp.2024.116071
Abstract

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.

Keywords

BCL6; FT671; P53; USP7 inhibitor; YCH2823; mTOR inhibitor.

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