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Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling

Authors
  • Lin, Chi-Chuan1
  • Suen, Kin Man1, 2
  • Stainthorp, Amy1
  • Wieteska, Lukasz1
  • Biggs, George S.3
  • Leitão, Andrei4
  • Montanari, Carlos A.4
  • Ladbury, John E.1, 5
  • 1 School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK
  • 2 Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
  • 3 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EQ, UK
  • 4 Medicinal Chemistry Group (NEQUIMED), São Carlos Institute of Chemistry, University of São Paulo (IQSC-USP), 13566-590, São Carlos, SP, Brazil
  • 5 Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
Type
Published Article
Journal
Cancer letters
Publication Date
Aug 10, 2019
Volume
457
Pages
86–97
Identifiers
DOI: 10.1016/j.canlet.2019.05.008
PMID: 31100409
PMCID: PMC6584941
Source
PubMed Central
Keywords
License
Unknown

Abstract

• Shc binds to Erk and sequesters it from MAPK signal transduction. • Inhibition of PTB domain binding to EGFR prevents release of Erk. • In silico screen identified indomethacin, a known NSAID, as an inhibitor for Shc PTB. • Indomethacin indirectly inhibits MAPK signalling by depriving the pathway of Erk. • The approach to MAPK inhibition through depleting free-Erk concentration is validated.

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