Hsp90 is a molecular chaperone that is responsible for the conformational maturation of more than 200 client protein substrates, many of which are directly associated with cell signaling, and thus, are often hijacked during malignant transformation. Consequently, through Hsp90 inhibition, multiple signaling pathways can be disrupted simultaneously. As a result, Hsp90 has emerged as a promising anti-cancer target, and there are currently 17 inhibitors undergoing clinical evaluation. Unfortunately, all of these molecule bind to the Hsp90 N-terminal binding site, and also induce the pro-survival heat shock response at the same concentration they inhibit the Hsp90 protein folding machinery. The net result is generally, cytostatic activity and the potential for chemotherapeutic resistance. Unlike N-terminal inhibitors, C-terminal inhibitors can segregate these activities, which have led to unforeseen opportunities for the development of useful anti-cancer agents. In fact, C-terminal inhibitors do not induce the heat shock response and consequently, induce apoptosis against many cancer cells with high differential selectivity. The first C-terminal inhibitor identified was novobiocin, which manifests an IC50 value of ~700 micromolar. During the past few years, we have modified this coumarin antibiotic and transformed it into a potential clinical lead compound that exhibits ~100 nM activity. In this proposal, we aim to further develop this class of compounds and to evaluate them in animal models of head and neck squamous cell carcinoma in an effort to provide additional evidence to support their clinical application against a varietyof cancers.

Public Health Relevance

Current Hsp90 inhibitors undergoing clinical evaluation exhibit detrimental properties that are proving difficult to overcome. We have identified molecules that do not exhibit these deleterious properties and instead, manifest exceptional activities in preliminary animal models of cancer. Thus, the goal of this application is to attack multiple cancer-enabling enzymes through the inhibition of Hsp90 at the C-terminus, which is under investigated and represents a promising paradigm for the development of useful anti-cancer agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA120458-10A1
Application #
8969542
Study Section
Special Emphasis Panel (ZRG1-OTC-C (03))
Program Officer
Fu, Yali
Project Start
2006-05-19
Project End
2019-06-30
Budget Start
2015-07-07
Budget End
2016-06-30
Support Year
10
Fiscal Year
2015
Total Cost
$372,418
Indirect Cost
$94,569
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
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Davis, Rachel E; Zhang, Zheng; Blagg, Brian S J (2017) A Scaffold Merging Approach to Hsp90 C-terminal Inhibition: Synthesis and Evaluation of a Chimeric Library. Medchemcomm 8:593-598

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