Fascin 1 (fascin) is an actin-bundling protein. It cross-links filamentous actin (F-actin) into tightly packed parallel bundles driving the formation of various cell surface protrusions, such as filopodia and invadopodia. They promote cell migration and invasion. Fascin 1 is either absent or shows low expression in normal epithelial tissues but shows overexpression in a number of cancers, with expression levels correlating with overall cancer aggressiveness and predicting poor clinical outcome. In a word, fascin is an actin-binding and bundling protein. It is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. In this study, BDP-13176 is a potent fascin 1 inhibitor. The Kd is 90 nM and the IC50 is 240 nM. BDP-13176 has potential as an anti-metastatic agent.
BDP-13176 further improves fascin affinity, giving us the best fascin binder (SPR Kd = 85 nM, ITC Kd = 50 nM) and actin-bundling inhibitor (IC50 = 240 nM). In addition, BDP-13176 (0-1 μM) inhibits fascin 1 bundling activity (seen as fascin and F-actin move from the pellet to the supernatant with increasing concentrations of BDP-13176).
Fascin, an actin-bundling protein, has relations with filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types. In addition, fascin forms stable actin bundles with slow dissociation kinetics in vitro. Fascin is important for invadopodia assembly and matrix degradation. In this study, fascin may be a viable target for anticancer/antimetastatic drugs. BDP-13176 is a useful foundation to further probe fascin’s potential role in tumor invasion and metastasis.
Francis S, et al. Bioorg Med Chem Lett. 2019;29(8):1023-1029.