title: Structure-based design of potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics.
abstract: Development of Grb2-SH2 domain antagonists is considered to be an effective and non-cytotoxic strategy to develop new antiproliferative agents because of their potential to shut down the Ras signaling pathway. We developed a concise route for the efficient synthesis of G1TE analogs on solid phase. Using this route, a series of cyclic peptides that do not rely on phosphotyrosine or its mimics were designed and synthesized based upon the phage library-derived cyclopeptide, G1TE. Considering that Gly7 plays prominent roles for G1TE binding to the Grb2-SH2 domain, we introduced different amino acids in the 7th position. The D-Ala7-containing peptide 3 demonstrates improved binding affinity by adopting favorable conformation for protein binding. This can be rationalized by molecular modeling. The optimization at the Leu2 position was also studied, and the resulting cyclopeptides exhibited remarkably improved binding affinity. Based upon these global modifications, a highly potent peptide ligand 9 was discovered with a Kd = 17 nM, evaluated by Biacore binding assay. This new analog is one of the most potent non-phosphorus-containing Grb2-SH2 antagonists reported to date. This potent peptidomimetic provides a new 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, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Jiang
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.forename: Lakshman
authors.initials: L
authors.lastname: Bindu
authors.forename: Karen W
authors.initials: KW
authors.lastname: Worthy
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: Marc
authors.initials: M
authors.lastname: Nicklaus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Roller
mesh_terms: D000409:Alanine / Q000737:chemistry; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010455:Peptides / Q000737:chemistry; D019000:Phosphotyrosine / Q000737:chemistry*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D018909:src Homology Domains
chemical_list: D051380:GRB2 Adaptor Protein; D010455:Peptides; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D000409:Alanine