The recent development of targeted protein kinase inhibitors has provided new opportunity 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. Thus, kinase inhibitors with more potent and selective properties and effectiveness against resistant mutants need to be developed. 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. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a new chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as non-small cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven tumors. Our results support the potential for the clinical evaluation of CH54242802 for long-term treatment of patients with ALK-driven tumors. CH5424802 is currently being investigated in Phase I/II clinical trials for patients with ALK-positive NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3559. doi:10.1158/1538-7445.AM2011-3559

©2011 American Association for Cancer Research
2011