title: 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.
abstract: 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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Hirosato
authors.initials: H
authors.lastname: Ebiike
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Taka
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohmori
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takami
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Hyohdoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Kohchi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Hayase
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nishii
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Nukinori
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shindoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C000602562:CH5183284; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor