title: Potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics.
abstract: Development of Grb2-SH2 domain antagonists is an effective approach to inhibit the growth of malignant cells by modulating Grb2-related Ras signaling. We report here potent Grb2-SH2 domain antagonists that do not rely on phosphotyrosine or its mimics. These non-phosphorylated antagonists were developed and further modified by constraining the backbone conformation and optimizing amino acid side chains of a phage library-derived peptide, G1TE. After extensive SAR studies and structural optimization, non-phosphorylated peptide 12 was discovered with an IC(50) of 75 nM. This potent peptidomimetic provides a novel template for the development of non-pTyr containing Grb2-SH2 domain antagonists and acts as a chemotherapeutic lead for the treatment of erbB2-related cancer.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, 21702, Frederick, MD, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Manchao
authors.initials: M
authors.lastname: Zhang
authors.forename: Ya Qiu
authors.initials: YQ
authors.lastname: Long
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.forename: Hongpeng
authors.initials: H
authors.lastname: Liu
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Marc
authors.initials: M
authors.lastname: Nicklaus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D002942:Circular Dichroism; D003198:Computer Simulation; D051380:GRB2 Adaptor Protein; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D019151:Peptide Library; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D018909:src Homology Domains / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; D008024:Ligands; D019151:Peptide Library; D011506:Proteins; D019000:Phosphotyrosine