Synthetic small-molecule prohormone convertase 2 inhibitors

Dorota Kowalska, Jin Liu, Jon R. Appel, Akihiko Ozawa, Adel Nefzi, Robert Mackin, Richard A. Houghten, Iris Lindberg

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 K i value for PC2 of 0.54 μM. In contrast, the most potent bicyclic guanidine inhibitor exhibited a K i value of 3.3 μM. Cross-reactivity with other convertases was limited: pyrrolidine bis-piperazines exhibited K i values greater than 25 μM for PC1/3 or furin, whereas the K i 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.

Original languageEnglish
Pages (from-to)617-625
Number of pages9
JournalMolecular Pharmacology
Volume75
Issue number3
DOIs
StatePublished - Mar 2009

Fingerprint

Proprotein Convertase 2
Piperazines
Guanidines
Proprotein Convertase 1
Furin
Libraries
Proprotein Convertases
Small Cell Carcinoma
Opioid Peptides
Peptide Hormones
Guanidine
Glucagon
Pancreas

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine

Cite this

Kowalska, D., Liu, J., Appel, J. R., Ozawa, A., Nefzi, A., Mackin, R., ... Lindberg, I. (2009). Synthetic small-molecule prohormone convertase 2 inhibitors. Molecular Pharmacology, 75(3), 617-625. https://doi.org/10.1124/mol.108.051334

Synthetic small-molecule prohormone convertase 2 inhibitors. / Kowalska, Dorota; Liu, Jin; Appel, Jon R.; Ozawa, Akihiko; Nefzi, Adel; Mackin, Robert; Houghten, Richard A.; Lindberg, Iris.

In: Molecular Pharmacology, Vol. 75, No. 3, 03.2009, p. 617-625.

Research output: Contribution to journalArticle

Kowalska, D, Liu, J, Appel, JR, Ozawa, A, Nefzi, A, Mackin, R, Houghten, RA & Lindberg, I 2009, 'Synthetic small-molecule prohormone convertase 2 inhibitors', Molecular Pharmacology, vol. 75, no. 3, pp. 617-625. https://doi.org/10.1124/mol.108.051334
Kowalska, Dorota ; Liu, Jin ; Appel, Jon R. ; Ozawa, Akihiko ; Nefzi, Adel ; Mackin, Robert ; Houghten, Richard A. ; Lindberg, Iris. / Synthetic small-molecule prohormone convertase 2 inhibitors. In: Molecular Pharmacology. 2009 ; Vol. 75, No. 3. pp. 617-625.
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