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Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido [2,3- d ]pyrimidin-7-one-based SOS1 inhibitor

文献类型：期刊论文

作者Wang, Kun5,6; Zhou, Zehui4,5; Ma, Xinyi3,6; Xu, Jiahang2,3,4; Xu, Wangyang5,6; Zhou, Guizhen1,3; Zhou, Chuan5; Li, Huajie2,4,5; Zheng, Mingyue2,3,4,6; Zhang, Sulin3,4
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2024-07-15
卷号107页码:9
关键词SOS1 KRAS mutation PROTAC Anti-cancer activity
ISSN号0960-894X
DOI10.1016/j.bmcl.2024.129780
通讯作者Zhang, Sulin(slzhang@simm.ac.cn) ; Xu, Tianfeng(tfxu@simm.ac.cn)
英文摘要Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3- d ]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC 50 values ranging from 1.85 to 7.53 nM. Mechanism studies demonstrated that 11o -induced SOS1 degradation was dependent on CRBN and proteasome. Moreover, 11o inhibited the phosphorylation of ERK and displayed potent anti-proliferative activities against SW620, A549 and DLD-1 cells. Further optimization of 11o may provide us promising SOS1 degraders with favorable drug-like properties for developing new chemotherapies targeting KRAS-driven cancers.
WOS关键词RAS ONCOGENES ; ACTIVATION ; DISCOVERY ; SON
资助项目Natural Science Foundation of Shanghai[20ZR1468500] ; Youth Innovation Promotion Association CAS[2023296]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001240513800001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/311567]  
专题新药研究国家重点实验室
通讯作者Zhang, Sulin; Xu, Tianfeng
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Kun,Zhou, Zehui,Ma, Xinyi,et al. Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido [2,3- d ]pyrimidin-7-one-based SOS1 inhibitor[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2024,107:9.
APA Wang, Kun.,Zhou, Zehui.,Ma, Xinyi.,Xu, Jiahang.,Xu, Wangyang.,...&Xu, Tianfeng.(2024).Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido [2,3- d ]pyrimidin-7-one-based SOS1 inhibitor.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,107,9.
MLA Wang, Kun,et al."Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido [2,3- d ]pyrimidin-7-one-based SOS1 inhibitor".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 107(2024):9.

入库方式： OAI收割

来源：上海药物研究所

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