title: An orthosteric inhibitor of the RAS-SOS interaction.
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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Nickerson
authors.affiliation: Department of Chemistry, New York University, New York, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Joy
authors.affiliation: Department of Chemistry, New York University, New York, USA.
authors.forename: Paramjit S
authors.initials: PS
authors.lastname: Arora
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, USA. Electronic address: Dafna.Bar-Sagi@nyumc.org.
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D051381:Rats; D020664:Son of Sevenless Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020664:Son of Sevenless Proteins; D018631:ras Proteins
keywords: Helical peptide inhibitor; Hydrogen bond surrogate; RAS; RASGEF; SOS