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Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

文献类型：期刊论文

作者Chen, Yating7; Liu, Qiupei3,5; Meng, Xianghui2; Cao, Wenxu4,5; Duo, Lihui3; Song, Xiaorong6; Shen, Xiangchun7; Low, Sze Shin3; Ho, Wan Yong1; Tang, Bencan3
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2025-09-01
卷号125页码:8
关键词SOS1 inhibitor KRAS mutation SOS1-KRAS interaction Resistance
ISSN号0960-894X
DOI10.1016/j.bmcl.2025.130282
通讯作者Tang, Bencan(bencan.tang@nottingham.edu.cn) ; Zhang, Pengli(zhangpengli@zidd.ac.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Xia, Guoqin(xiaguoqin@simm.ac.cn)
英文摘要The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could down-regulate the levels of phosphorylated ERK and AKT in the NCI-H358 cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven cancer.
WOS关键词AMG 510 ; RAS ; GTP
资助项目Zhongshan Science and Technology Bureau[CXTD2023009] ; Program for Young Talented Investigators of Guangdong Province[2021QN020533] ; Special Funds of the National Natural Science Foundation of China[82441046] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0120231001]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001498354700001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/318177]  
专题中国科学院上海药物研究所
通讯作者Tang, Bencan; Zhang, Pengli; Xie, Hua; Xia, Guoqin
作者单位1.Univ Nottingham Malaysia, Fac Med & Hlth Sci, Semenyih 43500, Malaysia
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210000, Peoples R China
3.Univ Nottingham Ningbo China, Fac Sci & Engn, Ningbo 315100, Peoples R China
4.Univ Chinese Acad Sci, Beijing 101408, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
7.Guizhou Med Univ, Sch Pharmaceut Sci, State Key Lab Discovery & Utilizat Funct Component, Guiyang 550014, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Yating,Liu, Qiupei,Meng, Xianghui,et al. Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2025,125:8.
APA Chen, Yating.,Liu, Qiupei.,Meng, Xianghui.,Cao, Wenxu.,Duo, Lihui.,...&Xia, Guoqin.(2025).Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,125,8.
MLA Chen, Yating,et al."Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 125(2025):8.

入库方式： OAI收割

来源：上海药物研究所

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