Small Molecule Therapeutics The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor Yoshito Nakanishi 1 , Nukinori Akiyama 1 , Toshiyuki Tsukaguchi 1 , Toshihiko Fujii 1 , Kiyoaki Sakata 1 , Hitoshi Sase 1 , Takehito Isobe 2 , Kenji Morikami 2 , Hidetoshi Shindoh 1 , Toshiyuki Mio, Hirosato Ebiike 1 , Naoki Taka 2 , Yuko Aoki 1 , and Nobuya Ishii 1 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/rearrange- ments. 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. Mol Cancer Ther; 13(11); 2547–58. Ó2014 AACR. Introduction In recent years, the use of molecular-targeted agents is increasingly adopted in basic and clinical cancer research with some of these drugs, improving patient survival times. In this context, a number of agents that target tyrosine kinases have been launched, such as the EGF receptor (EGFR) inhibitor erlotinib, the anti-HER2 anti- body trastuzumab, the BCR-ABL inhibitor imatinib, the B- RAF inhibitor vemurafenib, and the ALK inhibitor crizo- tinib. Each of these agents has demonstrable efficacy when used in patient cohorts that are stratified on the basis of the genetic status of their respective molecular targets. How- ever, such agents cannot cover all tumors, thus a medical need remains for novel agents against tumors harboring novel genetic alterations. Many tumors have genetic alterations in members of the receptor tyrosine kinase (RTK) family, which includes FGF receptors (FGFR). The FGFR family con- sists of FGFR1, FGFR2, FGFR3, and FGFR4, and each member is bound by a subset of 22 FGF ligands. The MAPK and PI3K/AKT pathways are critical down- stream mediators of FGFR signaling. In cancer, consti- tutive FGFR signaling is activated by gene amplifica- tion, point mutations, or chromosomal translocations/ rearrangements in several tumor types and is known to be involved in cell growth, angiogenesis, cell migration, invasion, and metastasis (1). Amplification of FGFR1 is one of the key genetic alterations in squamous cell lung carcinoma and hormone receptor–positive breast cancer (2–4). In addition, FGFR2 is also amplified in gastric and breast cancers (5, 6). Point mutations of FGFR2 and FGFR3 are mainly observed in endometrial cancer and bladder cancer, respectively (7–9). Furthermore, the explosion in next-generation sequencing technology has revealed several chromosomal translocations/rearran- gements of FGFR1, FGFR2, and FGFR3 in glioblastoma, bladder cancer, and breast cancer as well as in other tumor types (10–12). Thus, there is a clear clinical need for FGFR-selective inhibitors. 1 Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kana- gawa, Japan. 2 Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Corresponding Author: Yoshito Nakanishi, Research Division, Chugai Pharmaceutical Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. Phone: 81-467-47-6262; Fax: 81-467-46-5320; E-mail: nakanishiyst@chugai-pharm.co.jp doi: 10.1158/1535-7163.MCT-14-0248 Ó2014 American Association for Cancer Research. Molecular Cancer Therapeutics www.aacrjournals.org 2547 on February 7, 2016. © 2014 American Association for Cancer Research. mct.aacrjournals.org Downloaded from Published OnlineFirst August 28, 2014; DOI: 10.1158/1535-7163.MCT-14-0248