Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases

Anne Marie R. Dechert, James P. MacNamara, Sarah R. Breevoort, Emily R. Hildebrandt, Ned W. Hembree, Adam C. Rea, Duncan E. McLain, Stephen B. Porter, Walter K. Schmidt, Timothy Dore

Research output: Contribution to journalArticle

Abstract

Dipeptidyl (acyloxy)methyl ketones (AOMKs) have been identified as mechanism-based inhibitors of certain cysteine proteases. These compounds are also inhibitors of the integral membrane proteins Rce1p and Ste24p, which are proteases that independently mediate a cleavage step associated with the maturation of certain isoprenylated proteins. The enzymatic mechanism of Rce1p is ill-defined, whereas Ste24p is a zinc metalloprotease. Rce1p is required for the proper processing of the oncoprotein Ras and is viewed as a potential target for cancer therapy. In this study, we synthesized a small library of dipeptidyl AOMKs to investigate the structural elements that contribute to the inhibitor properties of this class of molecules toward Rce1p and Ste24p. The compounds were evaluated using a fluorescence-based in vitro proteolysis assay. The most potent dipeptidyl AOMKs contained an arginine residue and the identity of the benzoate group strongly influenced potency. A 'warhead' free AOMK inhibited Rce1p and Ste24p. The data suggest that the dipeptidyl AOMKs are not mechanism-based inhibitors of Rce1p and Ste24p and corroborate the hypothesis that Rce1p is not a cysteine protease.

Original languageEnglish (US)
Pages (from-to)6230-6237
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number17
DOIs
StatePublished - Sep 1 2010

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Ketones
Peptide Hydrolases
Modulation
Cysteine Proteases
Proteolysis
Cysteine Proteinase Inhibitors
Oncogene Proteins
Benzoates
Metalloproteases
Libraries
Arginine
Zinc
Assays
Membrane Proteins
Fluorescence
Molecules
Processing
Neoplasms
Proteins
Therapeutics

Keywords

  • (Acyloxy)methyl ketone
  • CaaX protein
  • Post-translational modification
  • Protease
  • Ras
  • Ras converting enzyme (Rce1p)
  • Sterile mutant 24 (Ste24p)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Dechert, A. M. R., MacNamara, J. P., Breevoort, S. R., Hildebrandt, E. R., Hembree, N. W., Rea, A. C., ... Dore, T. (2010). Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases. Bioorganic and Medicinal Chemistry, 18(17), 6230-6237. https://doi.org/10.1016/j.bmc.2010.07.041

Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases. / Dechert, Anne Marie R.; MacNamara, James P.; Breevoort, Sarah R.; Hildebrandt, Emily R.; Hembree, Ned W.; Rea, Adam C.; McLain, Duncan E.; Porter, Stephen B.; Schmidt, Walter K.; Dore, Timothy.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 17, 01.09.2010, p. 6230-6237.

Research output: Contribution to journalArticle

Dechert, AMR, MacNamara, JP, Breevoort, SR, Hildebrandt, ER, Hembree, NW, Rea, AC, McLain, DE, Porter, SB, Schmidt, WK & Dore, T 2010, 'Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases', Bioorganic and Medicinal Chemistry, vol. 18, no. 17, pp. 6230-6237. https://doi.org/10.1016/j.bmc.2010.07.041
Dechert, Anne Marie R. ; MacNamara, James P. ; Breevoort, Sarah R. ; Hildebrandt, Emily R. ; Hembree, Ned W. ; Rea, Adam C. ; McLain, Duncan E. ; Porter, Stephen B. ; Schmidt, Walter K. ; Dore, Timothy. / Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases. In: Bioorganic and Medicinal Chemistry. 2010 ; Vol. 18, No. 17. pp. 6230-6237.
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