发现一种治疗急性淋巴细胞白血病的强效、选择性和有效的 USP7 降解剂。

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-08-08 Epub Date: 2024-07-19 DOI:10.1021/acs.jmedchem.4c01134

Miaomiao Xu, Jingfeng Fu, Yuan Pei, Mengna Li, Weijuan Kan, Ruyu Yan, Chaoyue Xia, Jingkun Ma, Peipei Wang, Yan Zhang, Yue Gao, Yaxi Yang, Yubo Zhou, Jia Li, Bing Zhou

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引用次数: 0

摘要

USP7 是一种极具吸引力的癌症治疗靶点，尤其是野生型 p53 的急性淋巴细胞白血病（ALL）。在此，我们报告发现了 XM-U-14 作为一种强效、选择性和高效的 USP7 蛋白水解靶向嵌合体降解剂。XM-U-14在诱导RS4;11细胞系降解USP7方面的DC50值为0.74 nM，Dmax为93%，同时还能显著抑制ALL细胞的生长。XM-U-14 即使每天服用 5 毫克/千克，也能有效抑制 RS4;11 肿瘤的生长，肿瘤消退率达 64.7%，并且不会对小鼠造成任何毒性反应。XM-U-14 是一种很有前景的 USP7 降解剂，可用于进一步优化 ALL 的治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia.

查看原文本刊更多论文

Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia.

USP7 is an attractive therapeutic target for cancers, especially for acute lymphoblastic leukemia (ALL) with wild-type p53. Herein, we report the discovery of XM-U-14 as a highly potent, selective and efficacious USP7 proteolysis-targeting chimera degrader. XM-U-14 achieves DC₅₀ values of 0.74 nM and D_max of 93% in inducing USP7 degradation in RS4;11 cell lines, and also significantly inhibits ALL cell growth. XM-U-14 even at 5 mg/kg dosed daily effectively inhibits RS4;11 tumor growth with 64.7% tumor regressions and causes no signs of toxicity in mice. XM-U-14 is a promising USP7 degrader for further optimization for ALL treatment.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.