eprintid: 23373 rev_number: 16 userid: 1419 dir: disk0/00/02/33/73 datestamp: 2014-10-21 16:56:11 lastmod: 2019-02-02 15:57:16 status_changed: 2014-10-21 16:56:11 type: article metadata_visibility: show item_issues_count: 0 eprint_status: archive creators_name: Rice, RL creators_name: Rusnak, JM creators_name: Yokokawa, F creators_name: Yokokawa, S creators_name: Messner, DJ creators_name: Boynton, AL creators_name: Wipf, P creators_name: Lazo, JS creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: creators_email: pwipf@pitt.edu creators_email: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: PWIPF creators_id: title: A targeted library of small-molecule, tyrosine, and dual-specificity phosphatase inhibitors derived from a rational core design and random side chain variation ispublished: pub divisions: sch_as_chemistry full_text_status: public abstract: Tyrosine phosphatases (PTPases) dephosphorylate phosphotyrosines while dual-specificity phosphatases (DSPases) dephosphorylate contiguous and semicontiguous phosphothreonine and phosphotyrosine on cyclin dependent kinases and mitogen-activated protein kinases. Consequently, PTPases and DSPases have a central role controlling signal transduction and cell cycle progression. Currently, there are few readily available potent inhibitors of PTPases or DSPases other than vanadate. Using a pharmacophore modeled on natural product inhibitors of phosphothreonine phosphatases, we generated a refined library of novel, phosphate-free, small-molecule compounds synthesized by a parallel, solid-phase combinatorial-based approach. Among the initial 18 members of this targeted diversity library, we identified several inhibitors of DSPases: Cdc25A, -B, and -C and the PTPase PTP1B. These compounds at 100 μM did not significantly inhibit the protein serine/threonine phosphatases PP1 and PP2A. Kinetic studies with two members of this library indicated competitive inhibition for Cdc25 DSPases and noncompetitive inhibition for PTP1B. Compound AC-αα69 had a K(i) of approximately 10 μM for recombinant human Cdc25A, -B, and -C, and a K(i) of 0.85 μM for the PTP1B. The marked differences in Cdc25 inhibition as compared to PTP1B inhibition seen with relatively modest chemical modifications in the modular side chains demonstrate the structurally demanding nature of the DSPase catalytic site distinct from the PTPase catalytic site. These results represent the first fundamental advance toward a readily modifiable pharmacophore for synthetic PTPase and DSPase inhibitors and illustrate the significant potential of a combinatorial-based strategy that supplements the rational design of a core structure by a randomized variation of peripheral substituents. date: 1997-12-16 date_type: published publication: Biochemistry volume: 36 number: 50 pagerange: 15965 - 15974 refereed: TRUE issn: 0006-2960 id_number: 10.1021/bi971338h pmid: 9398331 mesh_headings: Binding, Competitive mesh_headings: Cell Cycle Proteins--antagonists & inhibitors mesh_headings: Drug Design mesh_headings: Enzyme Inhibitors--chemical synthesis mesh_headings: Enzyme Inhibitors--chemistry mesh_headings: Enzyme Inhibitors--metabolism mesh_headings: Enzyme Inhibitors--pharmacology mesh_headings: Escherichia coli--genetics mesh_headings: Humans mesh_headings: Kinetics mesh_headings: Molecular Structure mesh_headings: Okadaic Acid--pharmacology mesh_headings: Phosphoprotein Phosphatases--antagonists & inhibitors mesh_headings: Phosphoprotein Phosphatases--genetics mesh_headings: Phosphoprotein Phosphatases--metabolism mesh_headings: Protein Tyrosine Phosphatases--antagonists & inhibitors mesh_headings: Protein Tyrosine Phosphatases--genetics mesh_headings: Protein Tyrosine Phosphatases--metabolism mesh_headings: Recombinant Fusion Proteins--antagonists & inhibitors mesh_headings: Recombinant Fusion Proteins--metabolism mesh_headings: cdc25 Phosphatases chemical_names: Cell Cycle Proteins chemical_names: Enzyme Inhibitors chemical_names: Recombinant Fusion Proteins chemical_names: Okadaic Acid chemical_names: Phosphoprotein Phosphatases chemical_names: Protein Tyrosine Phosphatases chemical_names: cdc25 Phosphatases citation: Rice, RL and Rusnak, JM and Yokokawa, F and Yokokawa, S and Messner, DJ and Boynton, AL and Wipf, P and Lazo, JS (1997) A targeted library of small-molecule, tyrosine, and dual-specificity phosphatase inhibitors derived from a rational core design and random side chain variation. Biochemistry, 36 (50). 15965 - 15974. ISSN 0006-2960 document_url: http://d-scholarship-dev.library.pitt.edu/23373/1/licence.txt