Truseltiq

Infigratinib is a small molecule kinase inhibitor that targets fibroblast growth factor receptor (FGFR)1, FGFR2 and FGFR3 with in vitro half-maximal inhibitory concentration (IC50) values of 1.1, 1.0, and 2.0 nanomolar (nM), respectively. In vitro, infigratinib inhibited the activity of FGFR1 to FGFR3, but not FGFR4, kinase insert domain receptor (KDR) and other kinases, at clinically relevant concentrations. The major active metabolites of infigratinib, BHS697 and CQM157, showed similar in vitro binding activity as infigratinib towards FGFR1 to FGFR3, with similar less potent activity toward FGFR4, in binding affinity studies. Infigratinib inhibited FGFR1 to FGFR3 phosphorylation and signalling and decreased cell viability in cancer cell lines with activating FGFR amplifications, mutations and fusions that resulted in constitutive activation of FGFR signalling. Constitutive FGFR signalling can support the proliferation and survival of malignant cells. Infigratinib exhibited anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR1, FGFR2, or FGFR3 alterations, including two patient-derived xenograft models of cholangiocarcinoma that expressed distinct FGFR2 fusion proteins. Infigratinib demonstrated brain-to-plasma concentration ratios (based on antibiotics area under the plasma concentration time curve from time zero to infinity (AUC0-inf)) of 0.682 in rats after a single oral dose.