Synthesis of a C-terminally biotinylated macrocyclic peptide mimetic exhibiting high Grb2 SH2 domain-binding affinity.
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.
Shi
Zhen-Dan
ZD
Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, MD 21702, USA.
Liu
Hongpeng
H
Zhang
Manchao
M
Worthy
Karen M
KM
Bindu
Lakshman
L
Yang
Dajun
D
Fisher
Robert J
RJ
Burke
Terrence R
TR
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
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