Potent inhibition of protein-tyrosine phosphatase-1B using the phosphotyrosyl mimetic fluoro-O-malonyl tyrosine (FOMT).
To enhance PTP binding interactions, both inside and outside the pTyr binding pocket, a thioether-cyclized peptide has been designed based on the EGF receptor autophosphorylation sequence (EGFR988-993) "Asp-Ala-Asp-Glu-pTyr-Leu", in which the pTyr resiude has been replaced by the nonphosphorus-containing pTyr mimetic fluoro-O-malonyltyrosine (FOMT, 2). The resulting peptide 4 exhibits a Ki value of 170 nM, making it one of the most potent inhibitors of PTP1B yet reported.
Roller
P P
PP
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wu
L
L
Zhang
Z Y
ZY
Burke
T R
TR
D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D007202:Indicators and Reagents; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry
C098642:4'-O-(2-(2-fluoromalonyl))tyrosine; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010446:Peptide Fragments; D019000:Phosphotyrosine; D014443:Tyrosine; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases