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

doi:10.1016/j.ejmech.2024.117039

	Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors
	Qibang Sui; Yuanyang Zhou; Manjia Li; Dan Wang; Rongrong Cui; Xiaoying Cai; Jia Liu; Xiaofeng Wang; Dan Teng; Jingyi Zhou; Hui Hou; Sulin Zhang; Mingyue Zheng
	2025-01-15
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (IF:6.0[JCR-2023],6.1[5-Year])
ISSN	0223-5234
EISSN	1768-3254
卷号	282
发表状态	已发表
DOI	10.1016/j.ejmech.2024.117039
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.
关键词	Synthetic lethal MSI tumors WRN inhibitors Triazolo-pyrimidine derivatives
URL	查看原文
收录类别	SCI
语种	英语
资助项目	Strategic Priority Research Program of the Chinese Academy of sciences[XDB0850000] ; National Natural Science Foundation of China["T2225002","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","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
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:001361870500001
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/449042
专题	生命科学与技术学院_博士生物质科学与技术学院_博士生
共同第一作者	Yuanyang Zhou
通讯作者	Hui Hou; Sulin Zhang; Mingyue Zheng
推荐引用方式 GB/T 7714	Qibang Sui,Yuanyang Zhou,Manjia Li,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.
APA	Qibang Sui.,Yuanyang Zhou.,Manjia Li.,Dan Wang.,Rongrong Cui.,...&Mingyue Zheng.(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.
MLA	Qibang Sui,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).