A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models

Abstract

The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells and play an important role in tumor cell growth, survival, and migration as well as in maintaining tumor angiogenesis. Overexpression of FGFRs or aberrant regulation of their activities has been implicated in many forms of human malignancies. Therefore, targeting FGFRs represents an attractive strategy for development of cancer treatment options by simultaneously inhibiting tumor cell growth, survival, and migration as well as tumor angiogenesis. Here, we describe a potent, selective, small-molecule FGFR inhibitor, (R)-(E)-2-(4-(2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol, designated as LY2874455. This molecule is active against all 4 FGFRs, with a similar potency in biochemical assays. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship. LY2874455 also exhibits a 6-to 9-fold in vitro and in vivo selectivity on inhibition of FGF-over VEGF-mediated target signaling in mice. Furthermore, LY2874455 did not show VEGF receptor 2-mediated toxicities such as hypertension at efficacious doses. Currently, this molecule is being evaluated for its potential use in the clinic.

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

“…Similar results were observed in the panel of 14 cancer cell lines that contained FGFRs dysregulated by a variety of mechanisms. Since the onset of this work, several additional FGFR-targeted agents have been reported, including NVP-BGJ398 (47), AZD4547 (48), and LY2874455 (49), that have potent pan-FGFR activity in preclinical models. It remains to be shown which, if any, of these agents can be safely administered to patients at levels sufficient to inhibit FGFRs.…”

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…LY2874455 was active against cancer cells and xenograft models harboring specifi c activating FGFR alterations. Furthermore, LY2874455 did not show VEGFR2-mediated toxicity at effi cacious doses ( 74 ). Currently, this molecule is being clinically tested in a phase I trial (clinicaltrials.…”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…This includes AZD4547 , BGJ398 (Guagnano et al, 2011), LY2874455 (Zhao et al, 2011), TAS-120 (Ochiiwa et al, 2014), ARQ 087 (Dransfield et al, 2014), PD 173074 (Dimitroff et al, 1999), JNJ-42756493 (Tabernero et al, 2015), BLU9931 (Hagel et al, 2015), DEBIO 1347 (Nakanishi et al, 2014), FGF401 (Repana et al, 2015) and BAY-1163877 (Heroult et al, 2014). Due to the large amount of drugs we will only focus on those who are being evaluated in clinical trials (Table 2).…”