Version 2.1.1.0

Abstract

Grant Number:	1R43CA102853-01
PI Name:	ZHUANG, YAN
PI Email:	yuz3@psu.edu
PI Title:
Project Title:	Novel Inhibitors of Human N-Myristoyltransferase

Abstract: 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.

Thesaurus Terms:
acyltransferase, drug design /synthesis /production, enzyme inhibitor, neoplasm /cancer pharmacology
antineoplastic, apoptosis, chemical synthesis, combinatorial chemistry, cytotoxicity, fatty acylation, molecular dynamics, myristate, neoplasm /cancer chemotherapy, pharmacokinetics, recombinant protein
high performance liquid chromatography, laboratory mouse, mass spectrometry, terminal nick end labeling

Institution:	APOGEE BIOTECHNOLOGY CORPORATION
	245 CANDLEWYCK LN
	HERSHEY, PA 17033
Fiscal Year:	2003
Department:
Project Start:	01-AUG-2003
Project End:	31-JUL-2005
ICD:	NATIONAL CANCER INSTITUTE
IRG:	ZCA1

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