title: The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor.
abstract: The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan. nakanishiyst@chugai-pharm.co.jp.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Nukinori
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsukaguchi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Sakata
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sase
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shindoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan. Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mio
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Hirosato
authors.initials: H
authors.lastname: Ebiike
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Taka
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C000602562:CH5183284; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor