Members of the Ras family, implicated in many human cancers, are modified post-translationally, targeting them to the appropriate intracellular location. Ras and other-CaaX proteins undergo 3 sequential reactions: isoprenylation of the cysteine, in particular farnesylation by farnesyltransferase (FTase); proteolysis of the 3 terminal amino acids (-aaX); and a-carboxyl methylation of the isoprenylated cysteine. This process is crucial for membrane localization and thus activity of the key Ras oncoproteins. FTase inhibitors are being evaluated in clinical trials as cancer chemotherapeutic agents. Unfortunately, these compounds have surprisingly little effect on many Ras-transformed tumors. There is now growing interest in the subsequent enzymatic steps; proteolysis by Ras converting enzyme (Reel) and a-carboxyl methylation by isoprenylcysteine methyltransferase (Icmt) as alternative targets for the inhibition of Ras protein action. Carboxyl methylation is critical for the proper localization of Ras proteins in yeast and mouse cells. Given this important finding, we believe that Icmt represents an excellent target for chemotherapeutic intervention. We hypothesize that certain readily synthesized, isoprenoid-based inhibitors of Icmt will be valuable lead compounds for the development of anti-Ras cancer chemotherapeutic agents. Recent published and unpublished studies from our laboratories have demonstrated that modifications to both the amino modification and the isoprenoid unit of prenylcysteines can afford small-molecule inhibitors of Icmt.
The specific aims of this collaborative, interdisciplinary research proposal are as follows:
Aim 1) Novel farnesol analogs will be elaborated to the corresponding prenylcysteine derivatives, via a solid-phase synthetic protocol. These will then undergo further chemical modification to provide libraries of prenylcysteine derivatives.
Aim 2) These prenylcysteine derivatives will be assayed as potential inhibitors of Icmt, using high-throughput in vitro assay systems and well-characterized and robust single point assay procedures for Icmt activity.
Aim 3) The prenylcysteine analogues will be evaluated for their ability to block prenylcysteine methylation in vivo. Potent cell permeable inhibitors will be evaluated for their ability to mislocalize Ras, interfere with Ras-mediated signaling, block anchorage-independent growth of pancreatic ductal carcinoma, and block tumor growth in vivo. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA112483-01A2
Application #
7213662
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2007-01-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
1
Fiscal Year
2007
Total Cost
$260,775
Indirect Cost
Name
Purdue University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Bergman, Joel A; Hahne, Kalub; Song, Jiao et al. (2012) S-Farnesyl-Thiopropionic Acid (FTPA) Triazoles as Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase. ACS Med Chem Lett 3:15-19
Majmudar, Jaimeen D; Hodges-Loaiza, Heather B; Hahne, Kalub et al. (2012) Amide-modified prenylcysteine based Icmt inhibitors: Structure-activity relationships, kinetic analysis and cellular characterization. Bioorg Med Chem 20:283-95
Majmudar, Jaimeen D; Hahne, Kalub; Hrycyna, Christine A et al. (2011) Probing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitors. Bioorg Med Chem Lett 21:2616-20
Bergman, Joel A; Hahne, Kalub; Hrycyna, Christine A et al. (2011) Lipid and sulfur substituted prenylcysteine analogs as human Icmt inhibitors. Bioorg Med Chem Lett 21:5616-9
Donelson, James L; Hodges-Loaiza, Heather B; Henriksen, Brian S et al. (2009) Solid-phase synthesis of prenylcysteine analogs. J Org Chem 74:2975-81