title: Investigations of linker structure on the potency of a series of bidentate protein tyrosine phosphatase inhibitors.
abstract: Protein tyrosine phosphatases (PTPases) and protein tyrosine kinase (PTKases) regulate the phosphorylation and dephosphorylation of tyrosine residues in proteins, events that are essential for a variety of cellular functions. PTPases such as PTP1B and the Yersinia PTPase play an important role in diseases including type II diabetes and bubonic plague. A library of 67 bidentate PTPase inhibitors that are based on the alpha-ketocarboxylic acid motif has been synthesized using parallel solution-phase methods. Two aryl alpha-ketocarboxylic acids were tethered to a variety of different diamine linkers through amide bonds. The compounds were assayed in crude form against the Yersinia PTPase, PTP1B, and TCPTP. Six compounds were selected for further evaluation, in purified form, against the Yersinia PTPase, PTP1B, TCPTP, LAR, and CD45. These compounds had IC50 values in the low micromolar range against the Yersinia PTPase, PTP1B, and TCPTP, showed good selectivity for PTP1B over LAR, and modest selectivity over CD45. The correlation between linker structure and inhibitor activity shows that aromatic groups in the linker can play an important role in determining binding affinity in this class of inhibitors.
authors.affiliation: Department of Chemistry, Brown University, 324 Brook St. Box H, Providence, RI 02912, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Seto
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015007:Yersinia / Q000187:drug effects / Q000201:enzymology
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases