The aberrant signaling of fibroblast growth factor 19 (FGF19) through the fibroblast growth factor receptor 4 (FGFR4) in combination with the co-receptor β–klotho (KLB) has been shown to be essential for the initiation and maintenance of a subset of solid tumors, and in particular hepatocellular carcinomas (HCC). This presentation will discuss our rational for the selection of a 2-formyl quinoline starting point and the strategy behind the initial optimization into highly potent and selective, reversible-covalent inhibitors of the kinase activity of the FGFR4. Scaffold morphing to improve the physiochemical properties and for the metabolic stabilization of the aldehyde electrophile were required in order to obtain compounds that were suitable to demonstrate in vivo efficacy in tumor xenograft models after oral dosing. Further optimization then led to the identification of FGF401, our clinical first-in-class FGFR4 inhibitor.

Hit-selection and optimization strategy en route to FGF401, a reversible-covalent inhibitor of FGFR4 for the treatment of hepatocellular carcinoma

256th National Meeting (2018)

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