There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance is recognized as a characteristic trait of the disease, defined by the inability to respond to normal circulating levels of insulin, and is usuall closely associated with obesity. Recent data suggest an inflammatory link between obesity and insulin resistance. We hypothesize that the induction of a counter-inflammatory program downstream of NF?B plays a key role in preserving energy storage, reducing energy expenditure and ensuring that insulin resistance is maintained during obesity. To this end, we have searched for inhibitors of the noncanonical IKK's TBK1 and IKK?, and plan to develop these as new therapeutic modalities. We will pursue this plan with three aims: 1) We will development analogs of the newly discovered inhibitor amlexanox with increased potency and metabolic stability, using both medicinal chemistry and structure- based design approaches;2) We will develop novel inhibitors of IKK? and TBK1 that represent new chemical entities, driven by increased potency, improved pharmaceutical properties and in vivo activity in mouse models of obese type 2 diabetes;and 3) In order to support the clinical development of these new compounds, we will develop in vivo biomarkers for IKK?/TBK1 inhibition.

Public Health Relevance

Recent data indicate that the protein kinases IKKepsilon and TBK1 might be interesting new targets for discovery of drugs for obesity and Type 2 diabetes. We will follow new leads for developing drugs that block these enzymes, providing a novel approach to the treatment of these devastating diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK100319-01
Application #
8610448
Study Section
Special Emphasis Panel (ZRG1-EMNR-R (56))
Program Officer
Pawlyk, Aaron
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$594,912
Indirect Cost
$212,332
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109