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Article

Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy.

European journal of medicinal chemistry - 5 Jan 2023

Xiang Shuang, Wang Jie, Huang Huisi, Wang Zuqin, Song Xiaojuan, Zhou Yang, Jin Feng, He Xun, Zhang Zhi-Min, Tu Zhengchao, Ding Ke, Zhang Zhang, Lu Xiaoyun

Abstract excerpt

TRK xDFG mutation-induced acquired resistance of 1st generation inhibitors larotrectinib and entrectinib remains an unmet clinical need. Here we report a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based derivatives as selective type II TRK inhibitors by hybridization. A representative compound 12d potently inhibited TRKA/B/C and TRKAG667C with IC50 values of 3.3, 6.4, 4.3 and 9.4 nM, respectively. 12d...

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PMID: 36410169
DOI: 10.1016/j.ejmech.2022.114899

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