The development of new methods to treat cancer is greatly needed. In this application, we have identified a macrocyclic small molecule that exhibits high differential selectivity for cancer cells vs. normal cells and aim to develop more simplified analogs of this molecule in an effort to maximize efficiency as well as to decrease the overall number of steps, which will likely lead to clinically useful molecules for the treatment of cancer. In addition, we aim to interrogate the activity manifested by these compounds in both cellular and animal models of cancer, with the goal of providing preclinical data to support the use of such compounds for translational development.

Public Health Relevance

Natural products that manifest selective activities against some cancers continue to serve as leads for the development of new anti-cancer agents. However, often times such compounds are difficult to prepare or isolate, which limits their potential clinical application. In this application, macrocyclic natural products that manifest selective anti-cancer activity have been identified and a campaign to simplify their structure to enable the rapid production is proposed alongside cellular and in vivo studies, which is likely to produce compounds with clinical applications for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA216919-03
Application #
9454428
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fu, Yali
Project Start
2018-01-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
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
Lirov, Roy; Worden, Francis P; Cohen, Mark S (2017) The Treatment of Advanced Thyroid Cancer in the Age of Novel Targeted Therapies. Drugs 77:733-745