A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

Cell. 2016 Apr 21;165(3):643-55. doi: 10.1016/j.cell.2016.03.045.

Abstract

Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

Keywords: MAPK; PI3K; RAF; RAS; RAS-binding domain; rigosertib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Crystallography, X-Ray
  • Dimerization
  • Glycine / administration & dosage
  • Glycine / analogs & derivatives*
  • Glycine / chemistry
  • Glycine / pharmacology
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Pancreatic Neoplasms / drug therapy
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins B-raf / chemistry
  • Proto-Oncogene Proteins B-raf / metabolism
  • RNA-Binding Proteins / chemistry*
  • RNA-Binding Proteins / metabolism
  • Sequence Alignment
  • Signal Transduction / drug effects*
  • Sulfones / administration & dosage
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • ras Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • RNA-Binding Proteins
  • Sulfones
  • ON 01910
  • BRAF protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins B-raf
  • polo-like kinase 1
  • ras Proteins
  • Glycine