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
