Many human cancers, including breast and pancreatic cancers, harbor aberrant Stat3 that functions as a master regulator of events that promote tumor formation and progression. Blocking aberrant Stat3 activity induces cancer cell growth inhibition and apoptosis, and tumor regression in mouse models. Given the number of human tumors with aberrant Stat3 activity, there is a high commercial potential for Stat3 inhibitors as novel anticancer drugs. Moreover, effective and selective Stat3 inhibitors will provide excellent molecular probes to interrogate Stat3 signaling to advance our understanding of the molecular mechanisms by which this protein mediates carcinogenesis, and provide new directions to thwart the functions of the aberrant protein. By computational modeling that exploited the key structural requirements for Stat3 activation, together with in silico screening of the NCI's Diversity and Plated sets chemical libraries, we identified agents, NSC 42067, NSC 59263 and NSC 74859, as binders of Stat3-SH2 domain and inhibitors of Stat3 DNA-binding activity (IC50 of 65-86

Public Health Relevance

Many human cancers harbor abnormal Stat3 activity that functions as a master regulator of events that promote tumor formation and progression. Blocking abnormal Stat3 activity induces cancer cell growth inhibition, apoptosis, and tumor regression in mouse models. Effective and selective Stat3 inhibitors are excellent research tools to interrogate Stat3 signaling to advance our understanding of the mechanisms leading to cancer, and represent potential new anticancer agents. Our proposal defines the molecular and biological properties of novel agents as Stat3-selective inhibitors that possess antitumor activity and that may be suitable for development into novel anticancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA128865-04
Application #
8115186
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Lees, Robert G
Project Start
2008-09-10
Project End
2013-07-31
Budget Start
2011-09-16
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$223,913
Indirect Cost
Name
University of Hawaii
Department
Biology
Type
Schools of Earth Sciences/Natur
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
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