Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer

Abstract

Metastasis is one of the leading causes of cancer-related death worldwide. Fascin, a protein that bundles actin filaments to produce protrusions in cancer cells, plays a significant role in the enhancement of cell migration. This protein has been shown that the overexpression of this protein is related to the appearance of different types of cancer, such as colorectal cancer. In this study, we conducted in silico screening of the Enamine library, a compound library with a broad chemical space. Using a ligand-based virtual screening approach based on the pharmacophore model of G2, we identified the predicted inhibitors. First, these compounds were validated by physicochemical analysis. Differential scanning calorimetry (DSF) was used to study the binding between the predicted compounds and fascin protein, followed by an F-actin bundling assay to determine which compounds inhibited the bundling function of fascin. Z1362873773, which exhibited binding to fascin and inhibited F-actin bundling, was further tested in cell cultures to assess its effects on cancer cell viability and migration as well as in organoid models to evaluate potential cytotoxicity. Finally, we established a protocol that can be applied to discover anti-fascin agents from diverse compound libraries. A new molecule has been identified with considerable fascin inhibitory and migration-arresting capacity, which may lead to the development of new therapies to treat cancer.