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Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7 (8H)-one derivatives as potent USP1 inhibitors

文献类型：期刊论文

作者Li, Hongrui3,5,7,8; Liu, Ben-Jin2,6; Xu, Jiahao1,3,5,7; Song, Shan-Shan2; Ba, Ruixian3,5,7,8; Zhang, Junjie4,5,7; Huan, Xia-Juan2,4; Wang, Dun8; Miao, Ze-Hong2,4,6; Liu, Tongchao5,7
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-09-05
卷号275页码:18
关键词USP1 inhibitor Structure -activity relationships Olaparib-resistant cell
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.116568
通讯作者Liu, Tongchao(tongchao_liu@simm.ac.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/ OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.
WOS关键词UBIQUITIN
资助项目National Natural Sci- ence Foundation of China[82173658] ; National Natural Sci- ence Foundation of China[81773572] ; National Natural Sci- ence Foundation of China[82073875] ; National Natural Sci- ence Foundation of China[82204187]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001257615000001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/312014]  
专题新药研究国家重点实验室
通讯作者Liu, Tongchao; He, Jin-Xue; Xiong, Bing
作者单位1.Jiangxi Univ Chinese Med, Sch Pharm, Nanchang 330004, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
3.Yangtze Delta Drug Adv Res Inst, 100 Dongtinghu Rd, Nantong 226133, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
6.Nanchang Univ, Jiangxi Med Coll, Sch Pharm, Nanchang, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
8.Shenyang Pharmaceut Univ, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China
推荐引用方式
GB/T 7714		 Li, Hongrui,Liu, Ben-Jin,Xu, Jiahao,et al. Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7 (8H)-one derivatives as potent USP1 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,275:18.
APA Li, Hongrui.,Liu, Ben-Jin.,Xu, Jiahao.,Song, Shan-Shan.,Ba, Ruixian.,...&Xiong, Bing.(2024).Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7 (8H)-one derivatives as potent USP1 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,275,18.
MLA Li, Hongrui,et al."Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7 (8H)-one derivatives as potent USP1 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 275(2024):18.

入库方式： OAI收割

来源：上海药物研究所

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