title: Structure-based design and discovery of novel inhibitors of protein tyrosine phosphatases.
abstract: Protein tyrosine phosphatases (PTPs) are important in the regulation of signal transduction processes. Certain enzymes of this class are considered as potential therapeutic targets in the treatment of a variety of diseases such as diabetes, inflammation, and cancer. However, many PTP inhibitors identified to date are peptide-based and contain a highly charged phosphate-mimicking component. These compounds usually lack membrane permeability and this limits their utility in the inhibition of intracellular phosphatases. In the present study, we have used structure-based design and modeling techniques to explore catalytic-site directed, reversible inhibitors of PTPs. Employing a non-charged phosphate mimic and non-peptidyl structural components, we have successfully designed and synthesized a novel series of trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds as PTP inhibitors. This is the first time that an uncharged phosphate mimic is reported in the literature for general, reversible, and substrate-competitive inhibition of PTPs. It is an important discovery because the finding may provide a paradigm for the development of phosphatase inhibitors that enter cells and modify signal transduction.
authors.affiliation: SUGEN, Inc., 230 East Grand Ave., South San Francisco, CA 94080, USA. ping-huang@sugen.com
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Ramphal
authors.forename: James
authors.initials: J
authors.lastname: Wei
authors.forename: Congxin
authors.initials: C
authors.lastname: Liang
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Gerald
authors.initials: G
authors.lastname: McMahon
authors.forename: Cho
authors.initials: C
authors.lastname: Tang
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes; D008958:Models, Molecular; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D013450:Sulfones; D017027:Protein Tyrosine Phosphatases