We have previously shown that nitric oxide (NO) induces differentiation and apoptosis in acute myeloid leukemia (AML) cells. Glutathione S-transferases (GST) are involved in multi-drug resistance and are upregulated in AML isolates. We have designed a class of diazeniumdiolate prodrugs that release NO upon interaction with glutathione in a reaction catalyzed by GST. Screening a library of these compounds with extensive lead optimization has led to the identification of O2-(2,4-Dinitrophenyl) 1-[(4- ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS-K as the most active compound of this class. JS-K has shown potent anti-leukemic activity in vitro and in vivo. JS-K has challenging solubility properties. Preliminary pharmacologic studies have shown that JS-K reacts with blood components. The goal of this research project is the pre-clinical development of JS-K for the treatment of AML. For that purpose we will work on developing a nanoscale delivery system that will solubilize and stabilize JS-K in vivo. We will pursue the following aims: 1- Development of a micellar formulation for JS-K. Using Pluronics(r), we will develop a micellar formulation of JS-K aiming at enhancing its solubilization and decreasing its reactivity with blood components. 2- Study the pharmacologic properties of JS-K in a micellar formulation. Using micellar formulations developed in Aim 1, we will study the pharmacology of JS-K in mice. 3- Study the in vivo efficacy of a micellar formulation of JS-K in mouse leukemia models. Using the formulations developed in Aim 1, we will study the anti-leukemic properties of JS-K in vivo using AML xenograft models in NOD/SCID IL2R?null mice. At the completion of this work, we will have a workable formulation of JS-K for clinical development. This work will add to our armamentarium a new class of potent anti- leukemic agents.

Public Health Relevance

There is a great need for new drugs to treat Acute Myeloid Leukemia (AML). Work done in this project will develop a new drug called JS-K for the treatment of AML. This work will lead to great improvements in treatment of AML and other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129611-03
Application #
7759546
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2008-04-01
Project End
2012-12-31
Budget Start
2010-02-01
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$312,288
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112