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

文献类型：期刊论文

作者Xu, Miaomiao6,7; Fu, Jingfeng6,7; Pei, Yuan7; Li, Mengna5; Kan, Weijuan7; Yan, Ruyu4,6; Xia, Chaoyue6,7; Ma, Jingkun3,6,7; Wang, Peipei5; Zhang, Yan6,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-19
页码20
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c01134
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要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.
WOS关键词CANCER ; TARGET ; HAUSP ; TP53 ; DEGRADATION ; INHIBITION ; PROTEINS ; THERAPY ; MDM2
资助项目National Natural Science Foundation of China[81973166] ; Science and Technology Commission of Shanghai Municipality[22XD1424600] ; Natural Science Foundation of Shanghai[22ZR1474100] ; Taishan Scholar Foundation of Shandong Province[tsqn202306322] ; Shandong Laboratory Program[SYS202205] ; Shandong Provincial Natural Science Foundation[ZR2023JQ028] ; Guangdong High-level new RD Institute[2023000003] ; Guangdong High-level new RD Institute[2019B090904008] ; Guangdong High-level Innovative Research Institute[2021B0909050003]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001273668900001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312410]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Zhou, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Miaomiao,Fu, Jingfeng,Pei, Yuan,et al. Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:20.
APA Xu, Miaomiao.,Fu, Jingfeng.,Pei, Yuan.,Li, Mengna.,Kan, Weijuan.,...&Zhou, Bing.(2024).Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia.JOURNAL OF MEDICINAL CHEMISTRY,20.
MLA Xu, Miaomiao,et al."Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia".JOURNAL OF MEDICINAL CHEMISTRY (2024):20.

入库方式： OAI收割

来源：上海药物研究所

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