Abstract 2729: FGFR genetic alterations as a potential predictor of the sensitivity to CH5183284/Debio 1347, a selective FGFR inhibitor with a novel chemical scaffold

Abstract

The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplification, point mutation, or chromosomal translocation/rearrangement. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGFR or PDGFR family showed some clinical benefits in FGFR genetically altered patient populations. However, to achieve more potent and prolonged efficacy in such populations, a selective FGFR inhibitor is still needed. Here, we report identifying CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold as a FGFR inhibitor. By interacting with unique residues in the ATP binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 (IC50: 9.3 nM, 7.6 nM, and 22 nM), but does not effectively inhibit FGFR4 (IC50: 290 nM ), KDR (IC50: 2,100 nM) or other 34 kinases. At 100 nM, CH5183284/Debio 1347 only binds to 5 kinases in the KinomeScan panel, including FGFR1, FGFR2, and FGFR3. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 does not lead to significant changes in blood pressure in telemetry-instrumented rats. In addition, CH5183284/Debio 1347 has a preferential antitumor activity against cancer cells with FGFR genetic alterations in a panel of 327 cancer cell lines. Among them, 4 cancer cell lines have copy number variations (CNV) of FGFR1 (>2.2 fold), 2 cancer cell lines have chromosomal translocation of FGFR1 (FGFR1OP-FGFR1), 6 cancer cell lines have CNV of FGFR2 (>2.2 fold), 3 cancer cell lines have point mutation of FGFR2 (S252W, K310R, N549K), 3 cancer cell lines have chromosomal translocation of FGFR3 (FGFR3-TACC3, FGFR3-BAIAP2L1), and 2 cancer cell lines have point mutation of FGFR3 (S249C, Y373C). This preferential efficacy against cancers harboring genetic alterations in FGFR was also confirmed in mouse xenograft studies. These findings warrant further investigation of CH5183284/Debio 1347 in patients harboring FGFR genetic alterations. Clinical studies have been initiated. Citation Format: Yoshito Nakanishi, Nukinori Akiyama, Toshiyuki Tsukaguchi, Yukako Tachibana-Kondo, Toshihiko Fujii, Kiyoaki Sakata, Hitoshi Sase, Takehito Isobe, Yasuko Sato, Kenji Morikami, Hidetoshi Shindoh, Toshiyuki Mio, Hirosato Ebiike, Naoki Taka, Yuko Aoki, Nobuya Ishii. FGFR genetic alterations as a potential predictor of the sensitivity to CH5183284/Debio 1347, a selective FGFR inhibitor with a novel chemical scaffold. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2729. doi:10.1158/1538-7445.AM2014-2729

Discovery of 3-(5′-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation

“…10 (sunitinib), 15 11 (sorafenib), 16 12 (pazopanib), 17 and 13 (vandetanib) 18 (Figure 2), undesired side effects such as hypertension and bleeding have been reported. [19][20][21] Recently, medicinal chemists tend to develop more selective FGFR inhibitors, and several orally available FGFR selective inhibitors have been reported to enter clinical trials, for example, 4 (NVP-BGJ398), 22 5 (AZD4547), 23 6 (CH5183284), 24 and 7 (LY2874455) 25 (Figure 1). The 3,5-dimethoxy-phenyl moiety of 4 and 5 occupies the same hydrophobic pocket and forms a hydrogen bond with Asp641, which is identified by 8 (PD173074) to contribute to their selectivity for FGFR1; [26][27] similar interactions are also observed between 6 and FGFR1.…”

“…The 3,5-dimethoxy-phenyl moiety of 4 and 5 occupies the same hydrophobic pocket and forms a hydrogen bond with Asp641, which is identified by 8 (PD173074) to contribute to their selectivity for FGFR1; [26][27] similar interactions are also observed between 6 and FGFR1. 24 Therefore, it is possible that a common single mutation would confer resistance to these inhibitors, which is classified as a category of genetic alteration contributed to the resistance of FGFR inhibitors besides other categories of compensatory pathway activation and epithelial-to-mesenchymal transition, as revealed by limited studies. 24,[28][29][30] As illustrated in the binding model of 7 in the ATP binding site of FGFR3, 25 Additionally, a hydrogen bond between the pyridyl nitrogen and Asn236 in hydrophobic pocket is observed; this additional hydrogen bond increases FGFR binding affinity.…”

“…24 Therefore, it is possible that a common single mutation would confer resistance to these inhibitors, which is classified as a category of genetic alteration contributed to the resistance of FGFR inhibitors besides other categories of compensatory pathway activation and epithelial-to-mesenchymal transition, as revealed by limited studies. 24,[28][29][30] As illustrated in the binding model of 7 in the ATP binding site of FGFR3, 25 Additionally, a hydrogen bond between the pyridyl nitrogen and Asn236 in hydrophobic pocket is observed; this additional hydrogen bond increases FGFR binding affinity. We envisioned that the interaction between the pyridine fragment and the hydrophobic pocket might overcome the resistance of the former three FGFR selective inhibitors (4, 5, and 6) caused by the single mutation as discussed above.…”

“…To understand the ligand-protein interactions, we developed a binding model of compound 9 in the ATP binding site of FGFR1 with a known crystal structure of the FGFR1 kinase domain (PDB ID: 3WJ6). 24 As shown in Figure 3, compound 9 binds to the hinge region of the kinase and forms two hydrogen bonds with the carbonyl of Glu562 and the NH of Ala564; an additional hydrogen bond occurs between the carbonyl of Ala564 and N(1)-H of benzimidazole moiety; the benzimidazole moiety extends from the indazole 3-position toward solvent exposed region. In view of the high degree of homology of FGFR1 with FGFR3, it was reasonable to assume that 7 and 9 had similar binding patterns with FGFR in the hinge region and the 6 solvent exposed region.…”