Inhibitors of Ras–SOS Interactions

Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein–protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate‐limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still ‘undruggable’ for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras–SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small‐molecule modulators or peptide mimetics aimed at the interface of the Ras–SOS PPI. We emphasize, however, that even if such Ras–SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose “pathway drug cocktails”, that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal.