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Discovery, Optimization, and Evaluation of Novel Pyridin-2(1H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment

文献类型：期刊论文

作者Xu, Zichao1,3,4; Peng, Xia1; Zhang, Renjie2,3; Ji, Yinchun1; You, Mengke1,3; Wang, Danyi1,3; Shen, Yanyan1; Zheng, Mingyue1,2; Li, Chunpu1,2,3; Ai, Jing1,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-01-16
卷号67期号:2页码:1168-1183
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01645
通讯作者Li, Chunpu(lichunpu@simm.ac.cn) ; Ai, Jing(jai@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound 4 with a novel pyridin-2-(1H)-one scaffold. Through a combination of structure-based drug design and structure-activity relationship (SAR) study, compound 14q was identified as a potent TRK inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, 14q displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong in vivo tumor growth inhibition of 14q was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.
WOS关键词ACQUIRED-RESISTANCE ; NTRK FUSION ; ENTRECTINIB ; DERIVATIVES ; DESIGN
资助项目National Natural Science Foundation of China[81821005] ; Natural Science Foundation of China for Innovation Research Group[82130105] ; Natural Science Foundation of China for Innovation Research Group[82173834] ; Natural Science Foundation of China for Innovation Research Group[82273766] ; National Natural Science Foundation of China ; SA-SIBS Scholarship Program[2020282] ; SA-SIBS Scholarship Program[LG202103-02-06] ; Youth Innovation Promotion Association CAS[2020CXJQ02] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001151536600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/308978]  
专题新药研究国家重点实验室
通讯作者Li, Chunpu; Ai, Jing; Liu, Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Zichao,Peng, Xia,Zhang, Renjie,et al. Discovery, Optimization, and Evaluation of Novel Pyridin-2(1H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(2):1168-1183.
APA Xu, Zichao.,Peng, Xia.,Zhang, Renjie.,Ji, Yinchun.,You, Mengke.,...&Liu, Hong.(2024).Discovery, Optimization, and Evaluation of Novel Pyridin-2(1H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment.JOURNAL OF MEDICINAL CHEMISTRY,67(2),1168-1183.
MLA Xu, Zichao,et al."Discovery, Optimization, and Evaluation of Novel Pyridin-2(1H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment".JOURNAL OF MEDICINAL CHEMISTRY 67.2(2024):1168-1183.

入库方式： OAI收割

来源：上海药物研究所

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