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 language | English (US) |
|---|---|
| Pages (from-to) | 6230-6237 |
| Number of pages | 8 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 18 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2010 |
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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
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 journal › Article
}
TY - JOUR
T1 - Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases
AU - Dechert, Anne Marie R.
AU - MacNamara, James P.
AU - Breevoort, Sarah R.
AU - Hildebrandt, Emily R.
AU - Hembree, Ned W.
AU - Rea, Adam C.
AU - McLain, Duncan E.
AU - Porter, Stephen B.
AU - Schmidt, Walter K.
AU - Dore, Timothy
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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.
AB - 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.
KW - (Acyloxy)methyl ketone
KW - CaaX protein
KW - Post-translational modification
KW - Protease
KW - Ras
KW - Ras converting enzyme (Rce1p)
KW - Sterile mutant 24 (Ste24p)
UR - http://www.scopus.com/inward/record.url?scp=77955982513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955982513&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2010.07.041
DO - 10.1016/j.bmc.2010.07.041
M3 - Article
C2 - 20696584
AN - SCOPUS:77955982513
VL - 18
SP - 6230
EP - 6237
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 17
ER -