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Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors

文献类型：期刊论文

作者Xu, Zichao8; Liu, Yueling5,6,7; Wang, Peng4,8; Peng, Xia7; Cheng, Jiawei8; Ji, Yinchun7; Li, Xutong8; Lin, Dongze7; Zhao, Jing8; Chen, Songbin8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-05-29
卷号68期号:11页码:11484-11501
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00412
英文摘要First-generation TRK inhibitors have been effectively employed in clinical oncology treatments. However, acquired resistance frequently develops, primarily attributed to resistant TRK mutants, particularly the prevalent xDFG TRKAG667C mutation. Herein, we unveil the design of novel next-generation TRK inhibitors by leveraging a conformational restriction strategy, beginning with lead compound 7, which was previously discovered by our team. Among them, compound 10o exhibited superior antiproliferative activity in the Ba/F3-MPRIP-TRKAG667C cell line compared to selitrectinib, one of the most advanced selective next-generation TRK inhibitors, and it potently inhibited TRK kinase activity with high selectivity. Furthermore, 10oHCl showed promising pharmacokinetic profiles with good oral bioavailability in mice. In vivo treatment with 10oHCl led to a marked delay in tumor growth in a Ba/F3-MPRIP-TRKAG667C subcutaneous tumor model. Thus, our work offers valuable insights for the development of next-generation TRK inhibitors.
WOS关键词PAN-TRK ; DISCOVERY ; POTENT
资助项目National Natural Science Foundation of China[2023YFF1205104] ; National Key R&D Program of China[82273766] ; National Natural Science Foundation of China ; Shanghai Talent Program[SIMM0120231001] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[2020282] ; Youth Innovation Promotion Association CAS
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001499942500001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/318228]  
专题新药研究国家重点实验室
通讯作者Liu, Hong; Ai, Jing; Li, Chunpu
作者单位1.Xinjiang Med Univ, Coll Pharm, Urumqi 830011, Xinjiang, Peoples R China
2.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
4.China Pharmaceut Univ, Sch Pharm, Nanjing 211198, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Zichao,Liu, Yueling,Wang, Peng,et al. Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(11):11484-11501.
APA Xu, Zichao.,Liu, Yueling.,Wang, Peng.,Peng, Xia.,Cheng, Jiawei.,...&Li, Chunpu.(2025).Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors.JOURNAL OF MEDICINAL CHEMISTRY,68(11),11484-11501.
MLA Xu, Zichao,et al."Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors".JOURNAL OF MEDICINAL CHEMISTRY 68.11(2025):11484-11501.

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来源：上海药物研究所

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