دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling.
المؤلفون: Lin CC; School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK., Suen KM; School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK; Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK., Stainthorp A; School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK., Wieteska L; School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK., Biggs GS; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EQ, UK., Leitão A; Medicinal Chemistry Group (NEQUIMED), São Carlos Institute of Chemistry, University of São Paulo (IQSC-USP), 13566-590, São Carlos, SP, Brazil., Montanari CA; Medicinal Chemistry Group (NEQUIMED), São Carlos Institute of Chemistry, University of São Paulo (IQSC-USP), 13566-590, São Carlos, SP, Brazil., Ladbury JE; School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK; Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India. Electronic address: j.e.ladbury@leeds.ac.uk.
المصدر: Cancer letters [Cancer Lett] 2019 Aug 10; Vol. 457, pp. 86-97. Date of Electronic Publication: 2019 May 14.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
مواضيع طبية MeSH: Drug Repositioning*, Anti-Inflammatory Agents, Non-Steroidal/*pharmacology , Antineoplastic Agents/*pharmacology , Indomethacin/*pharmacology , MAP Kinase Signaling System/*drug effects , Neoplasms/*drug therapy , Shc Signaling Adaptor Proteins/*antagonists & inhibitors, Anti-Inflammatory Agents, Non-Steroidal/chemistry ; Anti-Inflammatory Agents, Non-Steroidal/metabolism ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Cell Movement/drug effects ; ErbB Receptors/chemistry ; ErbB Receptors/metabolism ; HeLa Cells ; Humans ; Indomethacin/chemistry ; Indomethacin/metabolism ; MCF-7 Cells ; Molecular Docking Simulation ; Neoplasm Invasiveness ; Neoplasms/enzymology ; Neoplasms/pathology ; Phosphorylation ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Shc Signaling Adaptor Proteins/chemistry ; Shc Signaling Adaptor Proteins/metabolism ; Structure-Activity Relationship
مستخلص: 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 Shc PTB 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.
(Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)
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معلومات مُعتمدة: 22356 United Kingdom CRUK_ Cancer Research UK; P41 GM103311 United States GM NIGMS NIH HHS; C57233/A22356 United Kingdom CRUK_ Cancer Research UK
فهرسة مساهمة: Keywords: Erk signalling; Mechanism of action; Shc PTB domain; Therapeutic repurposing
المشرفين على المادة: 0 (Anti-Inflammatory Agents, Non-Steroidal)
0 (Antineoplastic Agents)
0 (Shc Signaling Adaptor Proteins)
EC 2.7.10.1 (EGFR protein, human)
EC 2.7.10.1 (ErbB Receptors)
XXE1CET956 (Indomethacin)
تواريخ الأحداث: Date Created: 20190518 Date Completed: 20200427 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC6584941
DOI: 10.1016/j.canlet.2019.05.008
PMID: 31100409
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-7980
DOI:10.1016/j.canlet.2019.05.008