Upon an oxidative insult (from electrophiles or quinones), the cytosolic proteins Keap1 and Nrf2 are separated from each other and Nrf2 migrates to the nucleus, leading to the increased expression of several antioxidant proteins including QR1.
The first aim of this research is to identify the exact mechanism by which electrophiles uncouple Nrf2 from Keap1. To pinpoint the mechanism, the crystal structures of the Nrf2-Keap1 complex and post-dissociation Keap1 and Nrf2 will be determined. Once the mechanism is known, nonmutagenic antioxidant response activators can be synthesized for potential use in chemoprotection from cancer. In addition, many cancerous cells have a high concentration of QR1 and for this reason innocuous prodrugs could be designed to become cytotoxic when reduced in vivo by QR1.
The second aim of this research is to develop a structure-activity relationship (SAR) between prodrug moieties and QR1 for each of two known prodrug-QR1 binding orientations.
This aim will entail computing the crystal structures of six new prodrug-QR1 complexes and analyzing the results with statistics. When the overall QR1-induced prodrug SAR is known, QR1-dependant chemotherapy can be better localized to tumors. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM070410-05
Application #
7285613
Study Section
Special Emphasis Panel (ZRG1-F05 (29))
Program Officer
Toliver, Adolphus
Project Start
2003-09-12
Project End
2008-09-11
Budget Start
2007-09-12
Budget End
2008-09-11
Support Year
5
Fiscal Year
2007
Total Cost
$44,801
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218