Abstract 1361: Fragment based drug discovery of selective inhibitors of Fibroblast Growth Factor Receptor (FGFR)

Abstract

Abstract Recent data in a number of tumour types has implicated Fibroblast Growth Factor (FGF) and Fibroblast Growth Factor receptor (FGFR) signalling as being key to the molecular pathology of cancer. A fragment screening campaign was conducted against the tyrosine kinase domain of FGFR1 to detect low molecular weight compounds that bound to the hinge region of the kinase. The screening produced several fragment inhibitors (molecular weight <250 Da) in the micromolar range and their binding modes were confirmed by X-ray crystallography. We selected an imidazo[1,2-a]pyridine fragment that was 120 uM versus FGFR3 in the kinase inhibition bioassay. Subsequently, in the fragments-to-leads stage a detailed structural understanding of the binding interactions between the fragment and its protein kinase target, using X-ray crystallography, led to the identification of a 0.003 uM inhibitor of FGFR3 in the kinase bioassay, with significant selectivity versus VEGFR2 and FLT3. The poster will focus on the description of previously undescribed compounds bearing an imidazo[1,2-a]pyridine core scaffold where selectivity versus other protein kinases, for example FLT3, is obtained using the X-ray crystal structure and structure-based design. In summary we will illustrate how X-ray crystallography and fragment-based drug design (FBDD) can be used to discover compounds with activity in an FGFR driven xenograft model when dosed by the oral route. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1361. doi:10.1158/1538-7445.AM2011-1361