Inhibitors of Ras-SOS Interactions

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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

Funding

FundersFunder number
National Institutes of HealthHHSN261200800001E
U.S. Department of Health and Human Services
National Cancer InstituteZIABC010441
Frederick National Laboratory for Cancer Research
Government of South Australia
National Natural Science Foundation of China81473137, 81322046, 81302698
Program for New Century Excellent Talents in UniversityNCET-12-0355
Shanghai Minhang Health And Family Planning Commission20154Y0058
National Key Research and Development Program of China2015CB910403
Shanghai Rising-Star Program13A1402300

    Keywords

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

    Fingerprint

    Dive into the research topics of 'Inhibitors of Ras-SOS Interactions'. Together they form a unique fingerprint.

    Cite this