The development of new methods to treat cancer is greatly needed. The Hsp90 protein folding machinery has been the target of significant interest for the development of anti-cancer agents. However, Hsp90 is responsible for the folding of ~300 protein folding substrates, which may lead to undesired on-target toxicity and may be responsible for many of the Hsp90-targeted drugs that have failed in clinical trials. Through a structure-based approach, an isoform-selective inhibitor of Hsp90 has been identified and shown to exhibit good selectivity and affinity against particular cancers. Consequently, the goal of this application is to optimize this new inhibitory scaffold for great affinity/efficacy, to evaluate the role of a specific Hsp90 isoform in cancer, and to validate this isoform as a target for the treatment of bladder cancer.

Public Health Relevance

There are four Hsp90 isoforms that together, are responsible for the conformational maturation/activation of >300 client proteins. Due to the role played by these client proteins in signaling cascades, Hsp90 has evolved into a highly sought after target for the development of new anti-cancer agents. Unfortunately, detriments associated with pan-inhibition of all four Hsp90 isoforms have arisen, supporting the development of isoform-selective inhibitors. This application aims to develop Hsp90b-selective inhibitors for the potential treatment of bladder cancer, the fifth most common cancer in the US.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA222894-03
Application #
9922232
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Kondapaka, Sudhir B
Project Start
2018-05-08
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
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