Macrocyclization in the design of non-phosphorus-containing Grb2 SH2 domain-binding ligands.
Macrocyclization from the phosphotyrosyl (pTyr) mimetic's beta-position has previously been shown to enhance Grb2 SH2 domain-binding affinity of phosphonate-based analogues. The current study examined the effects of such macrocyclization using a dicarboxymethyl-based pTyr mimetic. In extracellular assays affinity was enhanced approximately 5-fold relative to an open-chain congener. Enhancement was also observed in whole-cell assays examining blockade of Grb2 binding to the erbB-2 protein-tyrosine kinase.
Shi
Zhen-Dan
ZD
Laboratory of Medicinal Chemistry, CCR, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Wei
Chang-Qing
CQ
Lee
Kyeong
K
Liu
Hongpeng
H
Zhang
Manchao
M
Araki
Toshiyuki
T
Roberts
Lindsey R
LR
Worthy
Karen M
KM
Fisher
Robert J
RJ
Neel
Benjamin G
BG
Kelley
James A
JA
Yang
Dajun
D
Burke
Terrence R
TR
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D045744:Cell Line, Tumor; D003500:Cyclization; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C485116:3-(2-amino-2-oxoethyl)-1,4,7-triaza-10-(4-(dicarboxymethyl)phenyl)-14-(1-naphthyl)-2,5,8-trioxo-6-pentamethylenecyclopentadecane-9-acetic acid; C495948:GRB2 protein, human