Novel Inhibitors of Human N-Myristoyltransferase

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R43CA102853-01
Agency Tracking Number: CA102853
Amount: $492,349.00
Phase: Phase I
Program: SBIR
Awards Year: 2003
Solicitation Year: N/A
Solicitation Topic Code: N/A
Solicitation Number: N/A
Small Business Information
PO BOX 916, HERSHEY, PA, 17033
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (717) 566-8635
Business Contact
Phone: (717) 520-9674
Research Institution
The goal of this project is to identify and characterize novel inhibitors of human N-myristoyltransferase (NMT) that are effective as cancer therapeutic agents. Studies have shown that NMT catalyzes critical steps in the processing of several oncoproteins, and that genetic inhibition of this process ablates carcinogenesis. NMT attaches a myristoyl lipid to the N-terminus of specific target proteins. This irreversible lipidation enables protein conformational changes, membrane association, and further posttranslational processing, all of which confer activity to these target proteins. Furthermore, NMT is overexpressed in various human cancers. This finding, in conjunction with the necessary processing of oncogene products, identifies NMT as a potential therapeutic target against cancer. Despite this accumulating evidence, pharmacological inhibition of NMT as a means of cancer therapy remains unexplored. To address this problem, we have initiated a project to discover and characterize small molecule inhibitors of human NMT. By developing a novel screening assay and testing a library of synthetic compounds, we identified two chemotypes that inhibit NMT activity: cyclohexyl-octahydro-pyrrolo[1,2- a]pyrazine (COPP) and adamantine-containing compounds (ACC). Compounds sharing these chemotypes were isolated from the library and demonstrated in vitro and in vivo potency. To develop proof of principle evaluations of the potential utility of these chemotypes, the following Specific Aims will be addressed in this project: 1. Design and synthesize analogs of cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazines and adamantine-containing compounds using QSAR and computational enzyme docking studies. 2. Evaluate these compounds using purified recombinant human NMT and cell-based assays. 3. Determine the in vivo toxicity, pharmacokinetics and antitumor activity of lead NMT inhibitors.

* Information listed above is at the time of submission. *

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