550P Preclinical characterization of CPL304110 as a potential selective inhibitor of fibroblast growth factors 1/2/3 in solid cancers

Abstract

Fibroblast Growth Factor Receptor (FGFR), a family of receptor tyrosine kinases (RTK) contains four members – FGFR1, FGFR2, FGFR3, FGFR4. FGFRs play a critical role in cell proliferation, migration, angiogenesis and survival. Dysregulation of FGF/FGFR signaling can result in formation of different tumour types including bladder, gastric, endometrial and lung cancer. Therefore, targeting FGFRs represents an attractive strategy for anticancer therapy for patients with FGFR-dependent tumours. Here we present CPL304110, a potent and selective small molecule that acts as FGFR 1/2/3 inhibitor. It can be a potential therapy for FGFRs dependent cancers. Activity of CPL304110 was evaluated against FGFRs in ADP-based enzymatic test and its selectivity was tested on KINOMEscan® screening platform. The biological potency of compound was evaluated in a number of cancer cell-based models using Western Blot and cell viability assay (ATPliteTM). Our inhibitor was also characterized in BioMAP Diversity PLUS panel. In vivo antitumour efficiency was verified on carcinoma xenograft models with FGFR1/2/3 aberrations: SNU-16, RT-112 and UM-UC-14. CPL304110 was designed as a novel, potent and selective FGFR1-3 inhibitor. CPL304110 showed strong inhibitory effect on FGFR2 (IC50 = 1.44 nM), FGFR1 (4.08 nM) and lower on FGFR3 (10.55 nM). Compound selectivity was evaluated on KINOMEscan® panel of 468 kinases at 1μM. We confirmed potent inhibitory activity on several FGFR-dependent cancer cell lines with low nanomolar IC50 values, without significant effect on viability of FGFR-independent cells (up to 33.7 μM). Cells treated with CPL304110 showed substantial decrease in activation of FGFR-mediated signaling. In the Diversity PLUS panel CPL304110 showed broad antiproliferative and anti-inflammatory impact. In vivo, oral administration of CPL304110 resulted in strong antitumour efficacy in all tested xenograft models. Presented preclinical studies indicated that CPL304110 can be qualified as a good clinical candidate for the treatment of FGFR-dependent tumours. Our drug is currently under clinical investigation – Phase I (NCT04149691).