Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes

Cancer Cell. 2015 Aug 10;28(2):170-82. doi: 10.1016/j.ccell.2015.07.001.

Abstract

Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chick Embryo
  • Female
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / chemistry
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Multimerization / drug effects*
  • Protein Structure, Tertiary
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • Xenograft Model Antitumor Assays / methods
  • Zebrafish
  • ras Proteins / metabolism*

Substances

  • DEL-22379
  • Indoles
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • ras Proteins