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J Biomol Screen

Title:		Small-molecule inhibitors of the Rce1p CaaX protease
Author(s):		Manandhar SP; Hildebrandt ER; Schmidt WK;
Address:		"Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA"
Journal Title:		J Biomol Screen
Year:		2007
Volume:		12
Issue:		7
Page Number:		983 - 993
DOI:		10.1177/1087057107307226
ISSN/ISBN:		1087-0571 (Print) 1552-454X (Electronic) 1087-0571 (Linking)
Abstract:		"The Rce1p protease is required for the maturation of the Ras GTPase and certain other isoprenylated proteins and is considered a chemotherapeutic target. To identify new small-molecule inhibitors of Rce1p, the authors screened the National Cancer Institute Diversity Set compound library using in vitro assays to monitor the proteolytic processing of peptides derived from Ras and the yeast a-factor mating pheromone. Of 46 inhibitors initially identified with a Ras-based assay, only 9 were effective in the pheromone-based assay. The IC(50) values of these 9 compounds were in the low micromolar range for both yeast (6-35 microM) and human Rce1p (0.4-46 microM). Four compounds were somewhat Rce1p selective in that they partially inhibited the Ste24p protease and did not inhibit Ste14p isoprenylcysteine carboxyl methyltransferase, 2 enzymes also involved in the maturation of isoprenylated proteins. The remaining 5 compounds inhibited all 3 enzymes. The 2 most Rce1p-selective agents were ineffective trypsin inhibitors, further supporting the specificity of these agents for Rce1p. The 5 least specific compounds formed colloidal aggregates, a proposed common feature of promiscuous inhibitors. Interestingly, the most specific Rce1p inhibitor also formed a colloidal aggregate. In vivo studies revealed that treatment of wild-type yeast with 1 compound induced a Ras2p delocalization phenotype that mimics observed effects in rce1 ste24 null yeast. The 9 compounds identified in this study represent new tools for understanding the enzymology of postisoprenylation-modifying enzymes and provide new insight for the future development of Rce1p inhibitors"
Keywords:		"Endopeptidases/*drug effects Hydrolysis Light Protease Inhibitors/*pharmacology Protein Prenylation Scattering, Radiation;"
Notes:		"MedlineManandhar, Surya P Hildebrandt, Emily R Schmidt, Walter K eng R03 NS053625-01/NS/NINDS NIH HHS/ R03/PHS HHS/ R01 GM067092/GM/NIGMS NIH HHS/ R01 GM067092-03/GM/NIGMS NIH HHS/ R01/PHS HHS/ R03 NS053625/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural 2007/10/19 J Biomol Screen. 2007 Oct; 12(7):983-93. doi: 10.1177/1087057107307226"