ZFIN ID: ZDB-PUB-170214-137
Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes
Herrero, A., Pinto, A., Colón-Bolea, P., Casar, B., Jones, M., Agudo-Ibáñez, L., Vidal, R., Tenbaum, S.P., Nuciforo, P., Valdizán, E.M., Horvath, Z., Orfi, L., Pineda-Lucena, A., Bony, E., Keri, G., Rivas, G., Pazos, A., Gozalbes, R., Palmer, H.G., Hurlstone, A., Crespo, P.
Date: 2015
Source: Cancer Cell   28: 170-82 (Journal)
Registered Authors: Hurlstone, Adam
Keywords: none
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*
PubMed: 26267534 Full text @ Cancer Cell
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.