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 o n the EGF receptor autophosphorylation sequence (EGFR(988-993)) ''Asp- Ala-Asp-GlU-pTyr-Leu'', in which the pTyr residue has been replaced by the nonphosphorus-containing pTyr mimetic fluoro-O-malonyltyrosine (F OMT, 2). The resulting peptide 4 exhibits a K-i value of 170 nM, makin g it one of the most potent inhibitors of PTP1B yet reported. (C) 1998 Elsevier Science Ltd. All rights reserved.