Examination of novel non-phosphorus-containing phosphotyrosyl mimetics against protein-tyrosine phosphatase-1B and demonstration of differential affinities toward Grb2 SH2 domains.
Inhibitory potencies were compared of several mono- and dicarboxy-based pTyr mimetics in Grb2 SH2 domain versus PTP1B assays. Although in both systems pTyr residues provide critical binding elements, significant differences in the manner of recognition exist between the two. This is reflected in the current study, where marked variation in relative potencies was observed between the two systems. Of particular note was the poor potency of all monocarboxy-based pTyr mimetics against PTP1B when incorporated into a hexapeptide platform. The recently reported high PTP1B inhibitory potency of similar phenylphosphate mimicking moieties displayed in small molecule, non-peptide structures, raises questions on the limitations of using peptides as platforms for pTyr mimetics in the discovery of small molecule inhibitors.
Gao
Y
Y
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wu
L
L
Luo
J H
JH
Guo
R
R
Yang
D
D
Zhang
Z Y
ZY
Burke
T R
TR
D048868:Adaptor Proteins, Signal Transducing; D002384:Catalysis; D051380:GRB2 Adaptor Protein; D006801:Humans; D018716:Molecular Mimicry; D019000:Phosphotyrosine / Q000737:chemistry / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000009:adverse effects*; D011506:Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D019000:Phosphotyrosine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases