Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

John M. Hatcher, Magda Bahcall, Hwan Geun Choi, Yang Gao, Taebo Sim, Rani George, Pasi A. Jänne, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of "second-generation" ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.

Original languageEnglish
Pages (from-to)9296-9308
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number23
Publication statusPublished - 2015 Dec 10

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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