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Optimization of direct small molecule inhibitors of Keap1-Nrf2 protein-protein interaction
Descriptive
TitleInfo
Title
Optimization of direct small molecule inhibitors of Keap1-Nrf2 protein-protein interaction
Name
(type = personal)
NamePart
(type = family)
Lee
NamePart
(type = given)
Sumi
NamePart
(type = date)
1984-
DisplayForm
Sumi Lee
Role
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(authority = RULIB)
author
Name
(type = personal)
NamePart
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Hu
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Lonqin
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Lonqin Hu
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Advisory Committee
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chair
Name
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NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
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School of Graduate Studies
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school
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Text
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theses
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2020
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2020-01
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2020
Language
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English
Abstract
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The Keap1-Nrf2-ARE signaling system that regulates the transcription and subsequent expression of cellular cytoprotective proteins and enzymes plays a crucial role in preventing pathological conditions exacerbated by the overproduction of oxidative stress. Thus, a noncovalent inhibitor that directly interrupts the Keap1-Nrf2 protein-protein interaction (PPI) and eventually leads to stimulation of related antioxidant responses has attracted a great deal of attention as a preventive and therapeutic agent for the treatment of oxidative stress-related diseases. Considering that the cellular potency or drug-like properties of direct inhibitors have remained as significant factors to be overcome, we have focused on discovering diverse classes of potent small molecule inhibitors based on known compounds via two different rational approaches. In this study, we found a series of 1,4-diamino phenyl and naphthalene scaffolds containing an oxygen-linked substituent that could be modified, contributing to greater structural diversity of the core moiety. The SAR studies revealed that O-linked derivatives displayed potent inhibitory activity in the submicromolar or nanomolar range. Among them, compound 120 is the most promising noncovalent inhibitor, with 64.5 nM in the fluorescent polarization (FP) assay and 14.2 nM in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. In addition, we designed three different scaffolds as direct inhibitors of Keap1-Nrf2 PPI via a molecular hybridization strategy, and identified THIQ and N-phenylglycine analogs which exhibited good potency for a preliminary SAR study. As a result, THIQ analog 139c was found to be the most potent with an IC50 value of 0.37 μM among a series of THIQ compounds developed by our group and other groups. Among the N-phenylglycine derivatives, compound 191b is the most active with an IC50 value of 183.4 nM in the FP assay and 107.5 nM in a TR-FRET assay. The optimized new scaffolds may serve as a promising starting point for further biological evaluation and rational optimization as a Nrf2 activator.
Subject
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Topic
Medicinal Chemistry
Subject
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Topic
Keap1
Subject
(authority = LCSH)
Topic
Protein-protein interactions
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Rutgers University Electronic Theses and Dissertations
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ETD_10503
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application/pdf
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text/xml
Extent
1 online resource (xi, 322 pages) : illustrations
Note
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Ph.D.
Note
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Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier
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doi:10.7282/t3-tjhg-ad70
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Lee
GivenName
Sumi
Role
Copyright Holder
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Type
Permission or license
DateTime
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2020-01-06 13:10:02
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Name
Sumi Lee
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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Embargo
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2020-01-31
DateTime
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2022-01-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 30th, 2022.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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