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The identification of molecular targets of synthetic oleanane triterpenoids

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Call No.	Ph.D. 2010
Author	Yore, Mark Michael
Title	The identification of molecular targets of synthetic oleanane triterpenoids
Date	2010
Abstract	Synthetic oleanane triterpenoids (SO) are a novel class of therapeutic compounds based on the structure of oleanolic acid. These synthetic oleanane triterpenoids which include 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), CDDO-methyl ester (CDDO-Me), and CDDO-imidazolide (CDDO-Im), are multi-functional electrophilic compounds and have demonstrated antiproliferative, antiangiogenic, proapoptotic, anti-inflammatory, and cytoprotective activities both in vitro and in vivo. While a great deal is known about the pharmacological effects of these compounds in cell culture systems and animal-disease models, there is a paucity of data pertaining to their direct molecular targets and underlying mechanisms of action. Herein, we sought to investigate further the molecular targets of these agents. We show that these compounds interact with reactive thiolate anions of cysteine, DTT and GSH in vitro thereby confirming that the SO can interact with sulfhydryl nucleophiles. We show that CDDO-Im and CDDO-Me are direct inhibitors of I?B kinase-beta (IKK?), and that they thereby inhibit binding of nuclear factor-?B (NF-?B) to DNA and subsequent transcriptional activation. CDDO-Im and CDDO-Me rapidly prevent I?B alpha (I?B?) phosphorylation and degradation in response to tumor necrosis factor alpha (TNF?). A biotinylated synthetic triterpenoid analog identified inhibitor-kappaB kinase (IKK) as a target of the SO. The SO bind directly to IKK and inhibit its kinase activity. Furthermore, we show that the target of the SO on IKK is a critical reactive cysteine residue, Cys179, in the activation loop of IKK. SO bind directly to Cys179 on IKK and thereby inhibit its activity. In additional studies, we utilized a biotinylated triterpenoid analog and proteomics to purify and identify 557 new, direct, targets for the SO. Bioinformatic analysis demonstrated that the SO pharmaco-interactome consists of a diverse, but interconnected set of signaling networks. From this dataset we confirmed that CDDO-Im and CDDO-Me directly interact with the mTOR Complex 1 (mTORC1) and thereby inhibits its kinase activity at nanomolar concentrations. Also, we show CDDO-Im possesses anti-diabetic properties. CDDO-Im enhances insulin-induced, insulin receptor (IR) phosphorylation levels. Further, CDDO-Im enhances downstream signaling from the IR and enhances glucose uptake in adipocytes in a PI3K-dependent manner by an as-yet, unidentified mechanism.
Description	xvi, 169 leaves : ill. 28 cm.
Format	application/pdf
Advisor	Sporn, Michael B. ; Dmitrovsky, Ethan ; Hwa, John ; Gerber, Scott ; Liby, Karen
Subject	Terpenes -- Mechanism of action. ; Protein kinases -- Inhibitors. ; Oleanolic Acid.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1694

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