Binding properties and biological characterization of new sugar-derived Ras ligands

Abstract

Since mutations of Ras genes have a great incidence in human tumours, Ras oncoproteins are a major clinical target for the development of anticancer agents. We have developed synthetic molecules able to inhibit Ras activation. Here we present new, water-soluble Ras inhibitors composed by an aromatic pharmacofore moiety covalently linked to different sugars. New glycosylated compounds bind to Switch 2 region of Ras, also involved in effector binding, inhibit GEF-catalyzed nucleotide exchange on Ras in vitro, and reduce Ras-dependent proliferation of murine fibroblasts. The influence of the sugar unit on Ras binding affinity and on the biological activity of Ras inhibitors has been investigated.