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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.
- Source :
-
Biochemistry [Biochemistry] 1997 Dec 16; Vol. 36 (50), pp. 15965-74. - Publication Year :
- 1997
-
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 microM 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-alphaalpha69 had a Ki of approximately 10 microM for recombinant human Cdc25A, -B, and -C, and a Ki of 0.85 microM 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.
- Subjects :
- Binding, Competitive
Cell Cycle Proteins antagonists & inhibitors
Enzyme Inhibitors chemistry
Enzyme Inhibitors metabolism
Escherichia coli genetics
Humans
Kinetics
Molecular Structure
Okadaic Acid pharmacology
Phosphoprotein Phosphatases genetics
Phosphoprotein Phosphatases metabolism
Protein Tyrosine Phosphatases genetics
Protein Tyrosine Phosphatases metabolism
Recombinant Fusion Proteins antagonists & inhibitors
Recombinant Fusion Proteins metabolism
cdc25 Phosphatases
Drug Design
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacology
Phosphoprotein Phosphatases antagonists & inhibitors
Protein Tyrosine Phosphatases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2960
- Volume :
- 36
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9398331
- Full Text :
- https://doi.org/10.1021/bi971338h