Computer-aided discovery of new FGFR-1 inhibitors followed by in vitro validation.

Abstract

FGFR-1 is an oncogenic kinase involved in several cancers. FGFR1-specific inhibitors have shown promising results against several human cancers prompting us to model this interesting target. Toward the end, we implemented elaborate ligand-based and structure-based computational workflows to explore the pharmacophoric requirements for potent FGFR-1 inhibitors. Results & methodology: Structure-based and ligand-based modeling applied on 59 diverse FGFR-1 inhibitors yielded novel pharmacophore and quantitative structure-activity relationship models that were used to scan the National Cancer Institute's structural database for novel leads. Four potent hits were captured, with the most active having IC50 of 426 nM. Identities and purities of active hits were established using nuclear magnetic resonance and mass spectroscopy. Elaborate ligand-based (pharmacophore/quantitaive structure-activity relationship) and structure-based (docking-based comparative intermolecular contacts analysis) modeling provided deep understanding of ligand binding within FGFR-1 as evidenced by the virtually captured new potent leads.