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Discovery of [5-Amino-1-(2-methyl‑3H‑benzimidazol-5-yl)pyrazol-4-yl]-(1H‑indol-2-yl)methanone (CH5183284/Debio 1347), An Orally Available and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor

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journal contribution
posted on 07.11.2016, 00:00 by Hirosato Ebiike, Naoki Taka, Masayuki Matsushita, Masayuki Ohmori, Kyoko Takami, Ikumi Hyohdoh, Masami Kohchi, Tadakatsu Hayase, Hiroki Nishii, Kenji Morikami, Yoshito Nakanishi, Nukinori Akiyama, Hidetoshi Shindoh, Nobuya Ishii, Takehito Isobe, Hiroharu Matsuoka
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations that drive activation of the receptors and the pathway are associated with tumor growth and survival; therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of 8 (CH5183284/Debio 1347), an orally available and selective inhibitor of FGFR1, FGFR2, and FGFR3. The chemical modifications, which were guided by 3D-modeling analyses of the inhibitor and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3. In in vitro studies and xenograft models in mice, 8 shows antitumor activity against cancer cell lines that harbor genetically altered FGFRs. These results support the potential therapeutic use of 8 as a new anticancer agent.