Journal article
Discovery and characterization of inhibitors of human palmitoyl acyltransferases
Molecular cancer therapeutics, Vol.5(7), pp.1647-1659
07/2006
Handle:
https://hdl.handle.net/2376/114539
PMCID: PMC2888271
PMID: 16891450
Abstract
The covalent attachment of palmitate to specific proteins by the action of palmitoyl acyltransferases (PAT) plays critical roles in the biological activities of several oncoproteins. Two PAT activities are expressed by human cells: type 1 PATs that modify the farnesyl-dependent palmitoylation motif found in H- and N-Ras, and type 2 PATs that modify the myristoyl-dependent palmitoylation motif found in the Src family of tyrosine kinases. We have previously shown that the type 1 PAT HIP14 causes cellular transformation. In the current study, we show that mRNA encoding HIP14 is up-regulated in a number of types of human tumors. To assess the potential of HIP14 and other PATs as targets for new anticancer drugs, we developed three cell-based assays suitable for high-throughput screening to identify inhibitors of these enzymes. Using these screens, five chemotypes, with activity toward either type 1 or type 2 PAT activity, were identified. The activity of the hits were confirmed using assays that quantify the in vitro inhibition of PAT activity, as well as a cell-based assay that determines the abilities of the compounds to prevent the localization of palmitoylated green fluorescent proteins to the plasma membrane. Representative compounds from each chemotype showed broad antiproliferative activity toward a panel of human tumor cell lines and inhibited the growth of tumors in vivo. Together, these data show that PATs, and HIP14 in particular, are interesting new targets for anticancer compounds, and that small molecules with such activity can be identified by high-throughput screening.
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Details
- Title
- Discovery and characterization of inhibitors of human palmitoyl acyltransferases
- Creators
- Charles E Ducker - Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, Box 250140, Charleston, SC 29425, USA. smithchd@musc.eduLindsay K GriffelRyan A SmithStaci N KellerYan ZhuangZuping XiaJohn D DillerCharles D Smith
- Publication Details
- Molecular cancer therapeutics, Vol.5(7), pp.1647-1659
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Publisher
- United States
- Grant note
- 2 R01 CA75248 / NCI NIH HHS R43 CA110071 / NCI NIH HHS 1 R43 CA110071 / NCI NIH HHS R01 CA075248-09 / NCI NIH HHS R01 CA075248 / NCI NIH HHS
- Identifiers
- 99900548084601842
- Language
- English
- Resource Type
- Journal article