title: Synthesis of a C-terminally biotinylated macrocyclic peptide mimetic exhibiting high Grb2 SH2 domain-binding affinity.
abstract: Although considerable effort has been devoted to developing Grb2 SH2 domain-binding antagonists, important questions related to ligand specificity, and identification of intracellular targets remain unanswered. In order to begin addressing these issues, the design, synthesis, and evaluation of a novel biotinylated macrocycle are reported that bears biotin functionality at a C-terminal rather than the traditional N-terminal position. With a Grb2 SH2 domain-binding K(eq) value of 3.4 nM, the title macrocycle (5) is among the most potent biotinylated SH2 domain-binding ligands yet disclosed. This should be a useful tool for elucidating physiological targets of certain Grb2 SH2 domain-binding antagonists.
authors.affiliation: Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
authors.forename: Hongpeng
authors.initials: H
authors.lastname: Liu
authors.forename: Manchao
authors.initials: M
authors.lastname: Zhang
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Lakshman
authors.initials: L
authors.lastname: Bindu
authors.forename: Dajun
authors.initials: D
authors.lastname: Yang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D019921:Biotinylation; D001943:Breast Neoplasms / Q000378:metabolism; D003500:Cyclization; D005260:Female; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D019000:Phosphotyrosine / Q000737:chemistry*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; D008024:Ligands; D010446:Peptide Fragments; D019000:Phosphotyrosine; D018719:Erb-b2 Receptor Tyrosine Kinases; C495948:GRB2 protein, human