Abstract 3593: Generation of a potent and selective inhibitor of ALK, CH5424802, showing superior oral bioavailability, PK profile and in vivo efficacy

Autor:	Noriyuki Furuichi, Nobuo Shimma, Hiroshi Sakamoto, Takuho Miyagi, Jun Ohwada, Kohsuke Asoh, Takuo Tsukuda, Kazutomo Kinoshita, Sosuke Hara, Yuko Aoki, Kazuo Hattori, Nobuya Ishii, Saori Taniguchi, Nobuhiro Oikawa, Kenji Takanashi, Toshiya Itoh, Toshiyuki Tsukaguchi, Hatsuo Kawada
Rok vydání:	2011
Předmět:	Cancer Research business.industry Kinase medicine.drug_class Cancer Pharmacology medicine.disease Fusion gene ALK inhibitor Oncology In vivo hemic and lymphatic diseases medicine Anaplastic lymphoma kinase Lung cancer business Tyrosine kinase
Zdroj:	Cancer Research. 71:3593-3593
ISSN:	1538-7445 0008-5472
DOI:	10.1158/1538-7445.am2011-3593
Popis:	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. It has been recognized as an attractive solid tumor target since the discovery in 2007 of the fusion gene, comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene, which is detected in ca. 6.7% of non-small-cell lung cancer (NSCLC) patients. We have identified a lead compound as an ALK inhibitor through kinase panel screening of in-house kinase-oriented library. The lead compound had a unique scaffold but showed a rather broad kinase inhibition profile. Therefore, we examined structure-activity relationship from the viewpoint of the kinase selectivity as well as ALK inhibition potency. Finally, we identified CH5424802 as a clinical candidate having high selectivity over other kinases including c-Met, c-Kit and KDR. CH5424802 has a preferable PK profile and good oral bioavailability in rats and monkeys. 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 both in vitro and in vivo. 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 3593. doi:10.1158/1538-7445.AM2011-3593
Databáze:	OpenAIRE
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