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The recent development of targeted protein kinase inhibitors has provided opportunities in cancer treatment. However, certain factors limit the efficacy of cancer therapies, such as a narrow therapeutic index caused by inhibition of multiple kinases, and the emergence of resistant mutants. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Especially, EML4-ALK has been identified as a fusion oncogene in non-small-cell lung cancer (NSCLC). We have carried out high-throughput screening of enzyme inhibitors against targets of tyrosine kinases, and we finally found CH5424802, a potent, selective, and orally available ALK inhibitor with a new chemical scaffold. In an enzyme inhibitory assay and a binding assay, CH5424802 had a nanomolar affinity with ATP-competitive inhibition mode. CH5424802 showed preferential antitumor activity against cancers with gene alterations of ALK, such as NSCLC cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma cells expressing NPM-ALK fusion in vitro and in vivo. It had a wide therapeutic index due to higher kinase selectivity. Acquired resistance to kinase inhibitors is one of the most serious problems in the long-term cancer treatment. In particular gatekeeper mutations are reported as one of the common resistant mechanisms of kinase inhibitors, such as ABL, EGFR, and KIT. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Potent ALK inhibitors effective against the gatekeeper mutants may offer clinical advantages in cancer treatment for patients with ALK-driven tumors.

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