trk受体
化学
激酶
药理学
医学
受体
生物化学
神经营养素
作者
Qiaohua Qin,Zhiqiang Guo,Shan Zhen Lu,Xin Wang,Qinglin Fu,Tianxiao Wu,Yixiang Sun,Nian Liu,Haoyu Zhang,Dongmei Zhao,Maosheng Cheng
标识
DOI:10.1016/j.ejmech.2023.115953
摘要
Tropomyosin receptor kinase (TRK) is a promising target for treating NTRK fusion cancers. The solvent front and xDFG mutations induced by larotrectinib and entrectinib result in acquired resistance in advanced-stage patients. In this study, we report a highly potent and selective type II TRK inhibitor, 40l, developed using a structure-based design strategy. Compound 40l significantly suppressed Km-12, Ba/F3-TRKAG595R, and Ba/F3-TRKAG667C cell proliferation. In biochemical and cellular assays, 40l showed better inhibitory activity against TRKAG667C than that by the positive control, selitrectinib. Additionally, it induced apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells in a dose-dependent manner. Furthermore, 40l showed good selectivity for a panel of 41 kinases. In vitro assays indicated that 40l possessed outstanding plasma stability and moderate liver microsomal stability. Based on the above results, compound 40l could be further optimized to overcome the solvent front and xDFG TRK mutations.
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