Abstract

Fascin 1 is an actin binding protein implicated and overexpressed in a range of aggressive and invasive tumor types and is believed to play a critical role in cancer cell metastasis. It cross-links filamentous actin (F-actin) into parallel bundles that are used in the formation of dynamic cellular protrusions such as lamellipodia and filopodia which are integral to cell migration, and in the formation of invadopodia used by tumor cell lines to degrade the tumor extracellular matrix (ECM). Utilising our in-house fragment collection (~1000 compounds) coupled with SPR, ITC and X-ray crystallography, we identified novel fascin 1 inhibitors binding in multiple ligand binding sites. Extensive optimisation delivered several series displaying nanomolar affinity in multiple biophysical as well as a novel Fluorescence Polarisation (FP) assay. The best of which includes BDP-00013176 (Kd≤85nM, IC50≤240nM). These lead compounds have now been tested in a number of cell based invasion assays including both 2D and 3D cultures, demonstrating the potential of fascin inhibition as a valid target for preventing invasion and metastasis.