Development of Non-Peptide Ligands of Growth Factor Receptor-Bound Protein 2-Src Homology 2 Domain Using Molecular Modeling and NMR Spectroscopy

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• 作者：Á ; ngel L. Orcajo-Rinco虂n ; Silvia Ortega-Gutie虂rrez ; Pedro Serrano ; Ivan R. Torrecillas ; Kurt Wu虉thrich ; Mercedes Campillo ; Leonardo Pardo ; Alma Viso ; Bellinda Benhamu虂 ; Mari虂a L. Lo虂pez-Rodri虂guez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 24, 2011
• 年：2011
• 卷：54
• 期：4
• 页码：1096-1100
• 全文大小：893K
• 年卷期：v.54,no.4(February 24, 2011)
• ISSN：1520-4804

文摘

We report a novel series of non-peptide ligands that inhibit the growth factor receptor-bound protein 2 (Grb2)-Src homology 2 (SH2) domain binding, designed using a combined computational and NMR-driven approach. We have identified a new lead compound, 1n (IC₅₀ = 56 渭M), which is cytotoxic in HER2-positive breast cancer cells and disrupts the interaction between HER2 and Grb2. Thus, 1n can be used as a scaffold for the development of efficient Grb2-SH2 domain binding inhibitors.