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 #
7R01CA120458-13
Application #
9600723
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fu, Yali
Project Start
2018-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Zhang, Zheng; You, Zhenyuan; Dobrowsky, Rick T et al. (2018) Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity. Bioorg Med Chem Lett 28:2701-2704
Khandelwal, Anuj; Kent, Caitlin N; Balch, Maurie et al. (2018) Structure-guided design of an Hsp90? N-terminal isoform-selective inhibitor. Nat Commun 9:425
Sanchez, Jaquelyn N; Wang, Ton; Cohen, Mark S (2018) BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers. Drugs 78:549-566
Kumar Mv, Vasantha; Ebna Noor, Radwan; Davis, Rachel E et al. (2018) Molecular insights into the interaction of Hsp90 with allosteric inhibitors targeting the C-terminal domain. Medchemcomm 9:1323-1331
Forsberg, Leah K; Davis, Rachel E; Wimalasena, Virangika K et al. (2018) Exploiting polarity and chirality to probe the Hsp90 C-terminus. Bioorg Med Chem 26:3096-3110
Zhang, Xinyue; Li, Chengyuan; Fowler, Stephen C et al. (2018) Targeting Heat Shock Protein 70 to Ameliorate c-Jun Expression and Improve Demyelinating Neuropathy. ACS Chem Neurosci 9:381-390
Garg, Gaurav; Zhao, Huiping; Blagg, Brian S J (2017) Design, synthesis and biological evaluation of alkylamino biphenylamides as Hsp90 C-terminal inhibitors. Bioorg Med Chem 25:451-457
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
Byrd, Katherine M; Kent, Caitlin N; Blagg, Brian S J (2017) Synthesis and Biological Evaluation of Stilbene Analogues as Hsp90 C-Terminal Inhibitors. ChemMedChem 12:2022-2029
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

Showing the most recent 10 out of 51 publications