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A targeted library of small-molecule, tyrosine, and dual-specificity phosphatase inhibitors derived from a rational core design and random side chain variation

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

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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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Rice, RL
Rusnak, JM
Yokokawa, F
Yokokawa, S
Messner, DJ
Boynton, AL
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JS
Date: 16 December 1997
Date Type: Publication
Journal or Publication Title: Biochemistry
Volume: 36
Number: 50
Page Range: 15965 - 15974
DOI or Unique Handle: 10.1021/bi971338h
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0006-2960
MeSH Headings: Binding, Competitive; Cell Cycle Proteins--antagonists & inhibitors; Drug Design; Enzyme Inhibitors--chemical synthesis; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--metabolism; Enzyme Inhibitors--pharmacology; Escherichia coli--genetics; Humans; Kinetics; Molecular Structure; Okadaic Acid--pharmacology; Phosphoprotein Phosphatases--antagonists & inhibitors; Phosphoprotein Phosphatases--genetics; Phosphoprotein Phosphatases--metabolism; Protein Tyrosine Phosphatases--antagonists & inhibitors; Protein Tyrosine Phosphatases--genetics; Protein Tyrosine Phosphatases--metabolism; Recombinant Fusion Proteins--antagonists & inhibitors; Recombinant Fusion Proteins--metabolism; cdc25 Phosphatases
PubMed ID: 9398331
Date Deposited: 21 Oct 2014 16:56
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/23373

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