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 #
5R01CA213566-03
Application #
9762054
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
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
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
Sanchez, Jaquelyn N; Wang, Ton; Cohen, Mark S (2018) BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers. Drugs 78:549-566
Subramanian, C; Kovatch, K J; Sim, M W et al. (2017) Novel C-Terminal Heat Shock Protein 90 Inhibitors (KU711 and Ku757) Are Effective in Targeting Head and Neck Squamous Cell Carcinoma Cancer Stem cells. Neoplasia 19:1003-1011
Khandelwal, Anuj; Crowley, Vincent M; Blagg, Brian S J (2017) Resorcinol-Based Grp94-Selective Inhibitors. ACS Med Chem Lett 8:1013-1018
Crowley, Vincent M; Huard, Dustin J E; Lieberman, Raquel L et al. (2017) Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer. Chemistry 23:15775-15782