Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

First Advisor

Patrick Woster

Second Advisor

Donald Menick

Third Advisor

Steven W. Kubalak

Fourth Advisor

Craig Beeson

Fifth Advisor

Zhi Zhong

Sixth Advisor

Campbell McInnes

Abstract

Current therapies to assist short- and long-term outcomes after acute myocardial infarction (AMI) depend on primary percutaneous coronary intervention shortly after ischemic insult. Upon reperfusion, localized influx of oxidative stressors overwhelms the endogenous antioxidant systems and lead to contractile dysfunction and arrhythmias. The extent of irreversible myocyte damage during ischemia-reperfusion (IR) injury is a key determinant in patient outcomes and therefore, strategies to reduce oxidative damage are essential. In recent years, increasing evidence indicates that epigenetic enzymes such as the histone demethylases and deacetylases play crucial roles during cardiovascular disease (CVD). One such enzyme, lysine specific demethylase-1 (LSD1), is hypoxia-inducible and regulates oxidative balance through epigenetic silencing of oxidative scavenging enzymes and production of hydrogen peroxide. Our predominant goal in this dissertation was to develop an LSD1 inhibitor with enhanced drug-like properties that is well tolerated by cardiac tissue and cardioprotective during IR. We identified a novel 3,5-diamino-1,2,4-triazoles scaffold that can be used to design potent, reversible, competitive LSD1 inhibitors that produce little or no overt cytotoxicity. Thus, the central hypothesis of this dissertation is that novel LSD1 inhibitors with enhanced drug-like properties can be used to mitigate cardiac ischemia-reperfusion structural damage and contractile dysfunction with minimal toxicity to myocytes. Our approach is innovative in that 1) we will design the first reported series of potent, reversible competitive inhibitors of LSD1 that display limited cytotoxicity, and 2) we will identify LSD1 as a new therapeutic target to mitigate myocardial IR injury. To accomplish this, we will focus on three aims. Specific Aim 1 - Perform hit-to-lead optimization through structural modification of a new small molecule scaffold to discover reversible LSD1 inhibitors with suitable efficacy, negligible toxicity and enhanced drug-like properties. Specific Aim 2 - Determine the LSD1 target selectivity, cellular cytotoxicity, and cellular phenotypic changes in histone methylation of lead compounds. Specific Aim 3 – evaluate the pharmacodynamic efficacy of a lead 3,5-diamino-1,2,4-triazole derivative to mitigate post-IR contractile dysfunction and infarction using two murine models of IR.

Rights

All rights reserved. Copyright is held by the author.

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