TitleModulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases.
Publication TypeJournal Article
Year of Publication2010
AuthorsDechert A-MR, MacNamara JP, Breevoort SR, Hildebrandt ER, Hembree NW, Rea AC, McLain DE, Porter SB, Schmidt WK, Dore TM
JournalBioorg Med Chem
Volume18
Issue17
Pagination6230-7
Date Published2010 Sep 1
ISSN1464-3391
KeywordsAntineoplastic Agents, Cysteine Proteases, Dipeptides, Drug Screening Assays, Antitumor, Ketones, Membrane Proteins, Metalloendopeptidases, Proprotein Convertases, Protease Inhibitors, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Substrate Specificity
AbstractDipeptidyl (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.
DOI10.1016/j.bmc.2010.07.041
Alternate JournalBioorg. Med. Chem.
PubMed ID20696584