Article
Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.
Journal of medicinal chemistry - 12 Jun 2014
Johnson Ted W, Richardson Paul F, Bailey Simon, Brooun Alexei, Burke Benjamin J, Collins Michael R, Cui J Jean, Deal Judith G, Deng Ya-Li, Dinh Dac, Engstrom Lars D, He Mingying, Hoffman Jacqui, Hoffman Robert L, Huang Qinhua, Kania Robert S, Kath John C, Lam Hieu, Lam Justine L, Le Phuong T, Lingardo Laura, Liu Wei, McTigue Michele, Palmer Cynthia L, Sach Neal W, Smeal Tod, Smith Graham L, Stewart Albert E, Timofeevski Sergei, Zhu Huichun, Zhu Jinjiang, Zou Helen Y, Edwards Martin P
Abstract excerpt
Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based...
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