Abstract DDT01-02: CH5424802: A selective ALK inhibitor

Abstract

Abstract Recent development of targeted protein kinase inhibitors provides new opportunity in cancer treatment. On the other hand, there are some cases limiting the efficacy of cancer therapies, owing to narrow therapeutic index by inhibiting multiple kinase, and the emergence of resistant mutants. Thus, the development of kinase inhibitors with more potent and selective properties and effectiveness to resistant mutants is needed. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in some cancers, due to gene alterations such as chromosomal translocation, amplification, or point mutation. Here we have identified CH5424802, a potent, selective and orally available ALK inhibitor with a new chemical scaffold. CH5424802 showed preferential antitumor activity against cancers with gene alterations of ALK, such as non-small cell lung cancer (NSCLC) cells expressing EML4-ALK fusion, anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion, and neuroblastoma with gene amplification of ALK in vitro and in vivo. Also, CH5424802 could inhibit ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and block the growth of EML4-ALK L1196M-driven cells. 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 DDT01-02. doi:10.1158/1538-7445.AM2011-DDT01-02