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

Author(s)

Lin, Chi-Chuan ^[1] ; Suen, Kin Man ^{[1, 2]} ; Stainthorp, Amy ^[1] ; Wieteska, Lukasz ^[1] ; Biggs, George S. ^[3] ; Leitao, Andrei ^[4] ; Montanari, Carlos A. ^[4] ; Ladbury, John E. ^{[1, 5]}

Affiliation

^[1] Univ Leeds, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire - England

^[2] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Tennis Court Rd, Cambridge CB2 1QN - England

^[3] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EQ - England

^[4] Univ Sao Paulo IQSC USP, Sao Carlos Inst Chem, Med Chem Grp NEQUIMED, BR-13566590 Sao Carlos, SP - Brazil

^[5] Indian Inst Technol, Dept Chem, Mumbai 400076, Maharashtra - India

• Document type: Journal article
• Source: Cancer Letters; v. 457, p. 86-97, 2019.
• Web of Science Citations: 0

Abstract

Receptor tyrosine kinase (RTK)-mediated hyperactivation of the MAPK/Erk pathway is responsible for a large number of pathogenic outcomes including many cancers. Considerable effort has been directed at targeting this pathway with varying degrees of long term therapeutic success. Under non-stimulated conditions Erk is bound to the adaptor protein Shc preventing aberrant signalling by sequestering Erk from activation by Mek. Activated RTK recruits Shc, via its phosphotyrosine binding (PTB) domain (Shc(PTB)), precipitating the release of Erk to engage in a signalling response. Here we describe a novel approach to inhibition of MAP kinase signal transduction through attempting to preserve the Shc-Erk complex under conditions of activated receptor. A library of existing drug molecules was computationally screened for hits that would bind to the ShcPTB and block its interaction with the RTKs EGFR and ErbB2. The primary hit from the screen was indomethacin, a non-steroidal anti-inflammatory drug. Validation of this molecule in vitro and in cellular efficacy studies in cancer cells provides proof of principle of the approach to pathway down-regulation and a potential optimizable lead compound. (AU)

• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Projects - Thematic Grants