Dysregulation of protein kinase activity has been implicated in a number of diseases, including cancer, diabetes, and chronic inflammation. Therefore, protein kinases have emerged as one of the most important drug targets in modern drug discovery. These efforts have resulted in the development of a vast array of small molecule inhibitors that interact with the ATP-binding sites of protein kinases and are able to block their catalytic activities. Interestingly, many of these pharmacological agents exploit the conformational flexibility of the ATP-binding sites of protein kinases by binding to different active site conformations. ATP-competitive inhibitors that stabilize different ATP-binding site conformations of multi-domain protein kinases have been shown to divergently affect domains and interactions outside of their active sites. This proposal will explore how stabilizing different active site conformations of Src-Family Kinases affect their sub-cellular localization, inter-molecular interactions, and signaling behavior. A suite of chemical genetic and chemical proteomic tools is proposed to explore the consequences of conformation-selective, Src-Family Kinase inhibition in diverse cellular contexts.

Public Health Relevance

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Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086858-12
Application #
9859404
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Barski, Oleg
Project Start
2008-09-30
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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