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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-R (56))
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Pawlyk, Aaron Christopher
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Beyett, Tyler S; Gan, Xinmin; Reilly, Shannon M et al. (2018) Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKK? and Reveal Mechanisms for Selective Inhibition. Mol Pharmacol 94:1210-1219
Zhao, Peng; Wong, Kai In; Sun, Xiaoli et al. (2018) TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. Cell 172:731-743.e12
Ahmadian, Maryam; Liu, Sihao; Reilly, Shannon M et al. (2018) ERR? Preserves Brown Fat Innate Thermogenic Activity. Cell Rep 22:2849-2859
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Yao, Xin-Qiu; Cato, M Claire; Labudde, Emily et al. (2017) Navigating the conformational landscape of G protein-coupled receptor kinases during allosteric activation. J Biol Chem 292:16032-16043
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