trk受体
突变体
原肌球蛋白受体激酶A
化学
激酶
原肌球蛋白
药物发现
抗药性
癌症研究
受体
药理学
生物化学
遗传学
生物
神经营养素
基因
肌球蛋白
作者
Lin-Sheng Zhuo,Mingshu Wang,Feng-Xu Wu,Haifeng Xu,Yi Gong,Zhi‐Cheng Yu,Ye Tian,Chao Pang,Ge‐Fei Hao,Wei Huang,Guang‐Fu Yang
标识
DOI:10.1021/acs.jmedchem.1c01539
摘要
Tropomyosin receptor kinase (TRK) inhibition is an effective therapeutic approach for treatment of a variety of cancers. Despite the use of first-generation TRK inhibitor (TRKI) larotrectinib (1) resulting in significant therapeutic response in patients, acquired resistance develops invariably. The emergence of secondary mutations occurring at the solvent-front, xDFG, and gatekeeper regions of TRK represents a common mechanism for acquired resistance. However, xDFG mutations remain insensitive to second-generation macrocyclic TRKIs selitrectinib (3) and repotrectinib (4) designed to overcome the resistance mediated by solvent-front and gatekeeper mutations. Here, we report the structure-based drug design and discovery of a next-generation TRKI. The structure-activity relationship studies culminated in the identification of a promising drug candidate 8 that showed excellent in vitro potency on a panel of TRK mutants, especially TRKAG667C in the xDFG motif, and improved in vivo efficacy than 1 and 3 in TRK wild-type and mutant fusion-driven tumor xenograft models, respectively.
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