CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant
Hiroshi Sakamoto, Toshiyuki Tsukaguchi, Sayuri Hiroshima, Tatsushi Kodama, Takamitsu Kobayashi, Takaaki A Fukami, Nobuhiro Oikawa, Takuo Tsukuda, Nobuya Ishii, Yuko Aoki, Hiroshi Sakamoto, Toshiyuki Tsukaguchi, Sayuri Hiroshima, Tatsushi Kodama, Takamitsu Kobayashi, Takaaki A Fukami, Nobuhiro Oikawa, Takuo Tsukuda, Nobuya Ishii, Yuko Aoki
Abstract
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 unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall 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 cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.
Copyright © 2011 Elsevier Inc. All rights reserved.
Source: PubMed