An Orthosteric Inhibitor of the RAS-SOS Interaction

Seth Nickerson, Stephen T. Joy, Paramjit Arora, Dafna Bar-Sagi

Research output: Contribution to journalArticle

Abstract

Rat sarcoma (RAS) proteins are signaling nodes that transduce extracellular cues into precise alterations in cellular physiology by engaging effector pathways. RAS signaling thus regulates diverse cell processes including proliferation, migration, differentiation, and survival. Owing to this central role in governing mitogenic signals, RAS pathway components are often dysregulated in human diseases. Targeted therapy of RAS pathways has generally not been successful, largely because of the robust biochemistry of the targets and their multifaceted network of molecular regulators. The rate-limiting step of RAS activation is Son of Sevenless (SOS)-mediated nucleotide exchange involving a single evolutionarily conserved catalytic helix from SOS. Structure function data of this mechanism provided a strong platform to design an SOS-derived, helically constrained peptide mimic as an inhibitor of the RAS-SOS interaction. In this chapter, we review RAS-SOS signaling dynamics and present evidence supporting the novel paradigm of inhibiting their interaction as a therapeutic strategy. We then describe a method of generating helically constrained peptide mimics of protein surfaces, which we have employed to inhibit the RAS-SOS active site interaction. The biochemical and functional properties of this SOS mimic support the premise that inhibition of RAS-nucleotide exchange can effectively block RAS activation and downstream signaling.

Original languageEnglish (US)
Pages (from-to)25-39
Number of pages15
JournalEnzymes
Volume34
DOIs
StatePublished - 2013

Fingerprint

Sarcoma
Rats
Nucleotides
Chemical activation
Peptides
Biochemistry
Physiology
Cues
Catalytic Domain
Ion exchange
Membrane Proteins
Survival
Therapeutics

Keywords

  • Helical peptide inhibitor
  • Hydrogen bond surrogate
  • RAS
  • RASGEF
  • SOS

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Biophysics
  • Molecular Biology

Cite this

An Orthosteric Inhibitor of the RAS-SOS Interaction. / Nickerson, Seth; Joy, Stephen T.; Arora, Paramjit; Bar-Sagi, Dafna.

In: Enzymes, Vol. 34, 2013, p. 25-39.

Research output: Contribution to journalArticle

Nickerson, Seth ; Joy, Stephen T. ; Arora, Paramjit ; Bar-Sagi, Dafna. / An Orthosteric Inhibitor of the RAS-SOS Interaction. In: Enzymes. 2013 ; Vol. 34. pp. 25-39.
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