Design and Characterization of a New Class of Inhibitors of Ras Activation

A bstract : The Ras proteins, which regulate intracellular signaling by a cyclic process involving interconversion between active GTP‐bound and inactive GDP‐bound states, play an essential role in controlling the activity of several crucial signaling pathways regulating normal cellular proliferation. Mutational activation of RAS genes can induce cancer in humans and other mammals. About 30% of human tumors contain an altered oncogenic Ras; therefore, inhibitors of Ras activation are potentially antineoplastic drugs. In this work we describe original molecules acting as Ras inhibitors. Recently a new class of inhibitors of the Ras nucleotide exchange process was described by Taveras et al. These molecules are able to form a noncovalent complex with Ras‐GDP, inhibiting the GDP‐GTP nucleotide exchange. We synthesized molecule SCH‐53870 and we found that it inhibits p21‐hRas nucleotide exchange in vitro , but it has very low solubility in water and undergoes rapid degradation at room temperature when dissolved in water‐DMSO mixtures. This chemical instability could prejudice pharmacological activity in vivo . With the aim to improve solubility and chemical stability, we designed and synthesized other original bioactive molecules that have been characterized in vitro using purified human and yeast Ras proteins and in vivo using suitable Saccharomyces cerevisiae strains. In the long term we hope that the knowledge we derive from these compounds will help in the development of an alternative therapy targeting Ras for a specific inhibition of transformed cell proliferation.