The 90 kDa heat shock proteins (Hsp90) are responsible for the maturation of approximately 200 client protein substrates, most of which are associated with signaling cascades that regulate cellular growth and proliferation. Therefore, Hsp90 inhibition provides a novel approach toward the treatment of cancer as numerous signaling cascades can be derailed through inhibition of the Hsp90-dependent protein folding process. In this application, we propose to develop selective inhibitors of the Hsp90 Isoforms, Grp94, Hsp90?, and Hsp90?, using a structure-guided approach. In addition, we will perform side by side evaluation of these compounds against pan-inhibitors both in vitro and in vivo to validate our approach. Together, these methods will provide a new approach for selective inhibition of Hsp90 and will provide a new paradigm for anti-cancer drug development.

Public Health Relevance

The development of cancer chemotherapeutics that exhibit minimal toxicity represents an emerging paradigm in medicinal chemistry/drug design. To diminish the detrimental properties associated with panHsp90 Inhibition, we will develop isoform-selective inhibitors of Hsp90 based on a rational drug design approach.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA213566-01A1
Application #
9379940
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2017-09-15
Project End
2021-08-31
Budget Start
2017-09-15
Budget End
2018-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556