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Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors

文献类型：期刊论文

作者Sui, Qibang1,8; Zhou, Yuanyang2,7; Li, Manjia3; Wang, Dan3; Cui, Rongrong1,4; Cai, Xiaoying1,4,6; Liu, Jia3; Wang, Xiaofeng1,4,6; Teng, Dan1,4; Zhou, Jingyi1,2,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-01-15
卷号282页码:21
关键词Synthetic lethal MSI tumors WRN inhibitors Triazolo-pyrimidine derivatives
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.117039
通讯作者Hou, Hui(houhuisdu@163.com) ; Zhang, Sulin(slzhang@simm.ac.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn)
英文摘要Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35. S35 exhibited excellent WRN helicase inhibitory activity (ADP-Glo kinase assay IC50 = 16.1 nM, fluorometric helicase assay IC50 = 23.5 nM). Additionally, S35 exhibited excellent cellular selectivity, with antiproliferative activity against multiple MSI cell lines (GI50 = 36.4-306 nM), while the GI50 values for multiple microsatellite stability (MSS) cell lines were greater than 20,000 nM. Furthermore, we observed that compound S35 induced DNA damage and caused G2/M cell cycle arrest in MSI cells, which did not occur in MSS cells. S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors.
WOS关键词CANCER ; HELICASE
资助项目Strategic Priority Research Program of the Chinese Academy of sciences[XDB0850000] ; National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program[E2G805H] ; Shanghai Municipal Science and Technology Major Project, National Key Research and Development Program of China[2023YFC2305904] ; Shanghai Municipal Science and Technology Major Project, National Key Research and Development Program of China[2022YFC3400504] ; Youth Innovation Promotion Association CAS[2023296] ; Young Elite Scientists Sponsorship Program by CAST[2023QNRC001] ; Natural Science Foundation of Shanghai[22ZR1474300]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001361870500001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/314695]  
专题中国科学院上海药物研究所
通讯作者Hou, Hui; Zhang, Sulin; Zheng, Mingyue
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Lingang Lab, Shanghai 200031, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
8.Ocean Univ China, Sch Med & Pharm, Chinese Minist Educ, Key Lab Marine Drugs, Qingdao 266003, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Sui, Qibang,Zhou, Yuanyang,Li, Manjia,et al. Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,282:21.
APA Sui, Qibang.,Zhou, Yuanyang.,Li, Manjia.,Wang, Dan.,Cui, Rongrong.,...&Zheng, Mingyue.(2025).Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,282,21.
MLA Sui, Qibang,et al."Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 282(2025):21.

入库方式： OAI收割

来源：上海药物研究所

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