Recent data in a number of tumor types have identified Fibroblast Growth Factors (FGF) and Fibroblast Growth Factor Receptors (FGFR) signaling as being key to the molecular pathology of cancer1. A fragment screening approach against FGFR1 was conducted at Astex Pharmaceuticals to detect low molecular weight compounds that bind to the hinge region of the kinase. The screen produced several fragment molecules and Astex identified an imidazopyridine hit as an interesting starting point due to its encouraging ligand efficiency value. This compound was further modified in order to provide potent in vitro and in vivo FGFR inhibitors displaying selectivity towards VEGFR22, 3 but also, towards Flt34.The design and the chemical access of the compounds as well as the influence of the different modifications on the kinase selectivity, the biological activities and the physicochemical properties will be presented and discussed.1 Beenken, A and Mohammadi, M. Nature Reviews-Drug discovery 2009  , 8, 235-2532 Squires, M. et al. Mol. Cancer Ther., 2011  , 10 (9), 1542-15523 Berdini, V. et al. WO2009/150240 A14 Saxty, G. et al. WO2010119285 A1

Imidazopyridine compounds as selective inhibitors of Fibroblast Growth Factor Receptors (FGFR)

245th National Meeting (2013)

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