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Molecular Pharmacology

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Research ArticleArticle

Synthetic Small-Molecule Prohormone Convertase 2 Inhibitors

Dorota Kowalska, Jin Liu, Jon R. Appel, Akihiko Ozawa, Adel Nefzi, Robert B. Mackin, Richard A. Houghten and Iris Lindberg
Molecular Pharmacology March 2009, 75 (3) 617-625; DOI: https://doi.org/10.1124/mol.108.051334
Dorota Kowalska
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Jin Liu
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Jon R. Appel
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Akihiko Ozawa
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Adel Nefzi
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Robert B. Mackin
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Richard A. Houghten
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Iris Lindberg
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Abstract

The proprotein convertases are believed to be responsible for the proteolytic maturation of a large number of peptide hormone precursors. Although potent furin inhibitors have been identified, thus far, no small-molecule prohormone convertase 1/3 or prohormone convertase 2 (PC2) inhibitors have been described. After screening 38 small-molecule positional scanning libraries against recombinant mouse PC2, two promising chemical scaffolds were identified: bicyclic guanidines, and pyrrolidine bis-piperazines. A set of individual compounds was designed from each library and tested against PC2. Pyrrolidine bis-piperazines were irreversible, time-dependent inhibitors of PC2, exhibiting noncompetitive inhibition kinetics; the most potent inhibitor exhibited a Ki value for PC2 of 0.54 μM. In contrast, the most potent bicyclic guanidine inhibitor exhibited a Ki value of 3.3 μM. Cross-reactivity with other convertases was limited: pyrrolidine bis-piperazines exhibited Ki values greater than 25 μM for PC1/3 or furin, whereas the Ki values of bicyclic guanidines for these other convertases were more than 15 μM. We conclude that pyrrolidine bis-piperazines and bicyclic guanidines represent promising initial leads for the optimization of therapeutically active PC2 inhibitors. PC2-specific inhibitors may be useful in the pharmacological blockade of PC2-dependent cleavage events, such as glucagon production in the pancreas and ectopic peptide production in small-cell carcinoma, and to study PC2-dependent proteolytic events, such as opioid peptide production.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA05084].

  • ABBREVIATIONS: PC, prohormone convertase; POMC, proopiomelanocortin; BSA, bovine serum albumin.

    • Received August 14, 2008.
    • Accepted December 10, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (3)
Molecular Pharmacology
Vol. 75, Issue 3
1 Mar 2009
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Research ArticleArticle

Synthetic Small-Molecule Prohormone Convertase 2 Inhibitors

Dorota Kowalska, Jin Liu, Jon R. Appel, Akihiko Ozawa, Adel Nefzi, Robert B. Mackin, Richard A. Houghten and Iris Lindberg
Molecular Pharmacology March 1, 2009, 75 (3) 617-625; DOI: https://doi.org/10.1124/mol.108.051334

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Research ArticleArticle

Synthetic Small-Molecule Prohormone Convertase 2 Inhibitors

Dorota Kowalska, Jin Liu, Jon R. Appel, Akihiko Ozawa, Adel Nefzi, Robert B. Mackin, Richard A. Houghten and Iris Lindberg
Molecular Pharmacology March 1, 2009, 75 (3) 617-625; DOI: https://doi.org/10.1124/mol.108.051334
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