Divalent and trivalent alpha-ketocarboxylic acids as inhibitors of protein tyrosine phosphatases.
Protein tyrosine phosphatases (PTPases) are important targets for the treatment of insulin resistance in patients with type II diabetes and as antibacterial agents. As a result, there is a growing interest in the development of potent and specific inhibitors for these enzymes. This paper describes a series of inhibitors that contain two or three alpha-ketocarboxylic acid groups that are designed to form multiple contacts with residues inside or near the active site of phosphatases. The inhibitors have been assayed against three PTPases: the Yersinia PTPase, PTP1B, and LAR. The best of the inhibitors has IC(50) values against the Yersinia PTPase and PTP1B of 0.7 and 2.7 microM, respectively. These divalent and trivalent compounds are significantly more potent than their corresponding monovalent analogues. In addition, they show good selectivity for PTP1B and the Yersinia PTPase as compared to LAR.
Department of Chemistry, Brown University, 324 Brook Street, Providence, Rhode Island 02912, USA.
Yen Ting
YT
Chen
Christopher T
CT
Seto
D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006038:Glyoxylates / Q000138:chemical synthesis* / Q000737:chemistry; D007651:Keto Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D015007:Yersinia / Q000737:chemistry
D004791:Enzyme Inhibitors; D006038:Glyoxylates; D007651:Keto Acids; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2