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Synthesis and biological evaluation of a targeted library of protein phosphatase inhibitors.

Wipf, P and Aslan, DC and Luci, DK and Southwick, EC and Lazo, JS (2000) Synthesis and biological evaluation of a targeted library of protein phosphatase inhibitors. Biotechnology and Bioengineering, 71 (1). 58 - 70. ISSN 0006-3592

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Phosphorylation of serine, threonine, and tyrosine controls fundamental mammalian cell events and is achieved by kinases which, in turn, are in dynamic relationship with phosphatases. Few selective inhibitors of protein tyrosine and dual specificity phosphatases are readily available. Based on SAR studies of naturally occurring phosphatase inhibitors and following up on previously published research, we have designed a new pharmacophore model V and synthesized a new library of functional analogues of V. All synthetic steps were carried out and optimized employing combinatorial chemistry methods on Wang resin. All compounds were tested in vitro for their ability to inhibit recombinant human protein tyrosine (PTP1B) and dual-specificity (Cdc25B(2) and VHR) phosphatases. Three of the approximately 70 compounds in our library inhibited Cdc25B(2) by 50% at 375-490 microM. No compounds inhibited PTP1B, and only one blocked VHR. Cell-culture studies revealed no toxicity to human breast cancer cells with two of the phosphatase inhibitors.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Wipf, Ppwipf@pitt.eduPWIPF
Aslan, DC
Luci, DK
Southwick, EC
Lazo, JS
Date: 2000
Date Type: Publication
Journal or Publication Title: Biotechnology and Bioengineering
Volume: 71
Number: 1
Page Range: 58 - 70
DOI or Unique Handle: 10.1002/(sici)1097-0290(200024)71:1<58::aid-bit9>;2-0
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
Uncontrolled Keywords: Databases as Topic, Drug Design, Enzyme Inhibitors, Ethers, Cyclic, Humans, Indicators and Reagents, Kinetics, Marine Toxins, Microcystins, Models, Molecular, Okadaic Acid, Oxazoles, Peptides, Cyclic, Phosphoprotein Phosphatases, Structure-Activity Relationship
ISSN: 0006-3592
Funders: NCI NIH HHS (CA78039)
MeSH Headings: Databases as Topic; Drug Design; Enzyme Inhibitors--chemical synthesis; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; Ethers, Cyclic--chemical synthesis; Ethers, Cyclic--chemistry; Ethers, Cyclic--pharmacology; Humans; Indicators and Reagents; Kinetics; Microcystins; Models, Molecular; Okadaic Acid--chemistry; Okadaic Acid--pharmacology; Oxazoles--chemical synthesis; Oxazoles--chemistry; Oxazoles--pharmacology; Peptides, Cyclic--chemical synthesis; Peptides, Cyclic--chemistry; Peptides, Cyclic--pharmacology; Phosphoprotein Phosphatases--antagonists & inhibitors; Structure-Activity Relationship
PubMed ID: 10629537
Date Deposited: 27 Feb 2014 16:50
Last Modified: 12 May 2021 19:22


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