title: Development of non-peptide ligands of growth factor receptor-bound protein 2-SRC homology 2 domain using molecular modeling and NMR spectroscopy.
abstract: 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 (IC(50) = 56 μM), 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.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Ángel L
authors.initials: ÁL
authors.lastname: Orcajo-Rincón
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Pedro
authors.initials: P
authors.lastname: Serrano
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Torrecillas
authors.forename: Kurt
authors.initials: K
authors.lastname: Wüthrich
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: Alma
authors.initials: A
authors.lastname: Viso
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human