Potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics.
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.
Li
Peng
P
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, 21702, Frederick, MD, USA.
Zhang
Manchao
M
Long
Ya Qiu
YQ
Peach
Megan L
ML
Liu
Hongpeng
H
Yang
Dajun
D
Nicklaus
Marc
M
Roller
Peter P
PP
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*
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; D008024:Ligands; D019151:Peptide Library; D011506:Proteins; D019000:Phosphotyrosine