Ras inhibition via direct Ras binding-is there a path forward?

Three decades after identification of the Ras oncogene, no effective treatments for Ras mutant tumors are available despite intensive drug discovery efforts. Here we critically review the attempts to inhibit Ras function via direct binding of small molecules at the Ras surface with the aim to disrupt its interaction with other proteins. Multiple binders at different binding sites have been discovered, and recent efforts afforded crystal structures of Ras-binder complexes. Albeit with low affinities, many of the binders were shown to impart inhibitory activities, and inhibition of nucleotide exchange as a consequence of disrupting the Ras-SOS interaction has been the most commonly identified mode of action. We see two key challenges in the development of these early starting points: Enhancing binding affinities and achieving selectivity, both against other GTPases and for mutant Ras over the wildtype form. In light of the large unmet medical need, we encourage the continued search for functionally active Ras binders, and we believe that integrated use of biophysical and biochemical tools will provide the highest chances for success. Given the failures experienced in the past and the significant hurdles ahead, we propose that this challenge be tackled through alliances between industry and academia. Published by Elsevier Ltd.