Identification of Small Molecule Inhibitors of I-κB Kinase Open Access
Yang, Xuesong (2010)
Abstract
Abstract
Identification of Small Molecule Inhibitors of I-κB
Kinase
By Xuesong Yang
Nuclear factor κB (NF-κB) transcription factor and its
pivotal role in many physiological and pathological processes have
been intensely studied for decades. Aberrant regulation of
NF-κB and its controlling signaling pathway can result in many
autoimmune diseases as well as cancer, making it a desirable
therapeutic target for drug development. Many natural products such
as curcumin have demonstrated their inhibition to NF-κB
signaling pathway, which contributes to their anticancer
therapeutic potential. To circumvent the problems of poor
bioavailability and low potency with curcumin, while retaining its
safety profile, many synthetic analogs derived from curcumin have
been developed. EF24, a monoketone analog of curcumin, has been
reported to have ten-fold better bioactivity than curcumin. In this
study, a novel class of compounds derived from curcumin was tested
for their anticancer activity. One compound, 3, 5-bis
[(6-chloropyridin-2-yl) methylidene]-1-methyl-4-piperidone, named
AM5, showed greater cytotoxic effect than EF24. Furthermore, AM5
was indicated to directly target NF-κB signaling pathway, by
effectively blocking the nuclear translocation of NF-κB,
impairing tumor necrosis factor (TNF)-α-induced I-κB
phosphorylation and degradation, and directly inhibiting the
catalytic activity of I-κB kinase. AM5 represents a new
structure of curcumin analogs that targets NF-κB signaling
more effectively, and the activities of compounds from the same
class have shed lights on further optimization and modification of
AM5 to improve its bioactivity for therapeutic application.
Identification of Small Molecule Inhibitors of I-κB
Kinase
By
Xuesong Yang
B.S., Wuhan University, 2008
Advisor: Dennis C. Liotta, Ph.D
Advisor: Haian Fu, Ph.D
A Thesis submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Master of Science
in Chemistry
2010
Table of Contents
Table of Contents
Chapter 1: Introduction...1
1.1 NF-κB...2
1.1.1 Introduction of NF-κB...2
1.1.2 The role of NF-κB in immune response...3
1.1.3 The role of NF-κB in tumorigenesis...4
1.1.4 NF-κB signaling pathway...5
1.1.4.1 Classical NF-κB signaling
pathway...5
1.1.4.2 Alternative NF-κB signaling pathway...6
1.1.5 Development of IKK inhibitors for therapeutic application...10
1.2 Curcumin...11
1.2.1 Introduction of curcumin...11
1.2.2 Therapeutic potential of curcumin...11
1.2.3 Therapeutic limitations of curcumin...12
1.2.4 Improving the pharmacological properties of curcumin...13
Chapter 2: Identification of a novel unsaturated monoketone analog of curcumin as a direct inhibitor of IKK-NF-κB signaling pathway...18
2.1 Introduction...19
2.2 Materials and Methods...19
2.3 Results...24
2.3.1 AM5 represents a favorable structure with
improved cytotoxicity over EF24...24
2.3.2 AM5 effectively impairs the nuclear translocation of
NF-κB...24
2.3.3 AM5 inhibits I-κB phosphorylation and degradation
induced by TNF-α...25
2.3.4 AM5 directly inhibits the catalytic activity of
IKKβ...26
2.4 Figure legends...28
Chapter 3: Discussion...41
List of Figures
Chapter 1
Figure 1.1 Members of NF-κB
family...7
Figure 1.2 Main members of I-κB family...8
Figure 1.3 Two classes of NF-κB signaling pathway...9
Figure 1.4 Structures of curcumin and EF24...15
Chapter 2
Figure 2.1 The core structure of compounds with
most improved cytotoxicity...31
Figure 2.2 AM5 exhibits better potency of cytotoxic effect than
EF24 in cancer cells...32
Figure 2.3 AM5 inhibits NF-κB nuclear translocation induced by
TNF-α...33
Figure 2.4 AM5 impairs TNF-α induced I-κB
phosphorylation...34
Figure 2.5 AM5 inhibits TNF-α induced I-κB
phosphorylation with a better potency than AM16...35
Figure 2.6 AM5 impairs TNF-α induced I-κB
degradation...36
Figure 2.7 AM5 directly inhibits the catalytic activity of
IKKβ...37
Chapter 3
Figure 3.1 Molecular mechanism for the action of AM5...45
List of Tables
Chapter 1
Table 1.1 Structures of AM compounds...16
Chapter 2
Table 2.1 IC50 (μM) values of
cell toxicity for all 17 AM compounds and EF24...38
Table 2.2 Ranking of IC50 values of cell toxicity for
all 17 AM compounds and EF24 39
Table 2.3 Ranking of IC50 values from NF-κB nuclear
translocation assay for all 17 AM compounds and EF24 40
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