Grants and Contracts Details
Description
Covalent modification by isoprenoid lipids (prenylation) is a critical post-translational event for many proteins
involved in cellular signaling and cancer. The primary goal of this research program is to design and test prenyl
function inhibitors and to identify and characterize proteins that are farnesylated in vivo. The studies outlined in
this proposal will result in the preparation of new tools to probe the specificity of the prenyltransferases proteinfarnesyltransferase
(FTase) and protein-geranylgeranyltransferase (GGTase-I), enable further development of
prenyl function inhibitors and identify new prenylated proteins as potential targets for therapeutic intervention.
By varying the chemical structure of the prenyl lipid, we are developing reagents to probe the biological
function of the posttranslational modification. Taking advantage of the fact that the prenyl group forms a
substantial part of the peptide substrate binding site in the prenyltransferases has allowed us to develop
peptide selective inhibitors of prenyl function. These unnatural analogues may allow for the selective
interference with specific prenylation targets and may provide lead compounds to alleviate the potential toxicity
associated with complete inhibition of protein prenylation. In particular, the unnatural analogues may be useful
to obtain a more complete understanding of the role that alternative prenylation plays in Farnesyl transferase
inhibitor (FTI) evasion by oncogenes such as K-Ras. Critical to understanding the clinical effects of existing
and future FTls and geranylgeranyl transferase inhibitors (GGTls), is the identification of in vivo substrates of
FTase and GGTase-1. Our innovative strategy of using unnatural, transferable prenyl analogues and analogue
specific monoclonal antibodies to identify prenylated cellular proteins will provide valuable information on the
cellular targets of inhibitors of prenylation. We expect these studies to result in the identification of previously
unknown prenylated proteins. The specific aims of this project are: 1) Synthesis of farnesyl and geranylgeranyl
diphosphate analogues to study protein prenylation. 2) Screening these compounds for ubstrate specificity of
FTase and GGTase-1 and development of prenyl function inhibitors. 3) Identification of prenylated proteins in
cells. The results from these studies may provide leads to new molecules to treat cancer and also identify new
molecular targets to develop anti-cancer therapies.
Status | Finished |
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Effective start/end date | 5/1/02 → 3/31/14 |
Funding
- National Institute of General Medical Sciences: $1,255,788.00
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