The mammalian fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) family comprises 22 FGF ligands, 18 of which exert their action through 4 highly conserved transmembrane tyrosine kinase receptors (FGFR1, FGFR2, FGFR3 and FGFR4). This highly complex signaling network regulates fundamental developmental pathways, physiological processes in the adult organism and a variety of cellular functions including proliferation, differentiation, and survival. Owing to such prominent roles, it is not surprising that different types of FGF/FGFR alterations, such as abnormal expression, mutations, and amplifications, have been found in diverse tumor types. A growing body of evidence linking deregulation of the FGF/FGFR system to the pathogenesis of cancer makes these receptors attractive targets for therapeutic intervention by a small molecular weight inhibitor approach.

We have established a new and non-conventional strategy to mimic documented lead compounds which consists in the replacement of real rings by stable pseudo six-membered rings resulting from the formation of an intramolecular hydrogen bond in a planar conjugated system. More recently, we have reported an example of the application of such strategy to the design of a new class of protein kinase inhibitors featuring a N-pyrimidin-4-yl-urea motif as an alternative to the pyrido[2,3-d]pyrimidin-7-one core structure of a well-known class of protein kinase inhibitors. In this context, we have described a prototype compound displaying submicromolar activity against several tyrosine kinases including FGFR1. In this communication we illustrate the process, guided by the use of molecular modeling and biochemical and cellular assays, that led to the identification of NVP-BGJ398, a potent and selective FGFR antagonist currently in phase I clinical trial.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B246.