Rational discovery of small molecule inhibitor targeting invasion and tumor growth

Abstract Rational targeting of proteins involved in controlling cancer cell behavior with small bioactive compounds can accelerate anti-cancer drug discovery. We report the identification of a new small molecule compound inhibitor of the FGFR adaptor protein FRS2. Pharmacophore-based computational screening combined with functional, biophysical, and structural binding analyses, led to the identification of low-molecular weight ligands that interact with the PTB domain of FRS2. By assessing the compounds’ anti-invasion activity in human FGFR-driven cancer cell models, three chemically distinct bioactive molecules were shortlisted for further analysis. A lead compound was selected that specifically repressed FGFR-driven MAPK activation and matrix invasion and displayed on-target activity in cells. Proteome-wide off-target activity of the primary lead was determined and functional in vivo efficacy in an FGFR driven ovarian cancer model confirmed. We propose inhibition of FRS2 by a small molecular PTB domain ligand as a strategy to repress FGF signaling in FGFR-driven human cancers.