Inhibitors of Ras-SOS Interactions

Shaoyong Lu, Hyunbum Jang, Jian Zhang*, Ruth Nussinov

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)814-821
Number of pages8
JournalChemMedChem
Volume11
Issue number8
DOIs
StatePublished - 19 Apr 2016

Keywords

  • H-Ras
  • K-Ras
  • KRAS
  • oncogenic mutations
  • peptide mimetics
  • protein-protein interactions

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