The long-term objectives of the proposed research program are to correlate the biochemical action of protein tyrosine kinases with cellular behavior. These enzymes play a crucial, but still often enigmatic role, in the signal transduction pathways responsible for cell growth and differentiation. Upon loss of key regulatory controls, either through over-expression or mutation, the oncogenic potential of these enzymes is released. Selective inhibitors, ligands, and sensors will be extraordinarily helpful in deciphering the role of these enzymes in specific pathways. In addition, inhibitors of kinase action may ultimately lay the foundation upon which therapeutically useful compounds can be devised. In particular, the primary focus of this research program deals with two key tyrosine kinases implicated in T cell activations. Consequently, inhibitors could furnish new therapies for autoimmune disorders, T cell derived cancers, and AIDs. The proposed research program seeks to expand upon our development of low nM affinity agents that target the SH1, SH2, and SH3 domains of tyrosine kinases, as well as sensors that allow us to fluorescently follow kinase activity.
Specific aims i nclude: (1) the acquisition of selective inhibitors/ligands that target the SH1, SH2, and SH3 domains of Fyn and Lck, (2) the preparation of selective fluorescent sensors of both enzymes, (3) the construction of caged inhibitors and sensors, and (4) the application of the chemical tools developed in aims 1 - 3 to explore the role of Fyn and Lck in T cell activation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079954-11
Application #
7802962
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Knowlton, John R
Project Start
1999-07-01
Project End
2011-11-30
Budget Start
2010-06-01
Budget End
2011-11-30
Support Year
11
Fiscal Year
2010
Total Cost
$281,986
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Rodgers, Zachary L; Shell, Thomas A; Brugh, Alexander M et al. (2016) Fluorophore Assisted Photolysis of Thiolato-Cob(III)alamins. Inorg Chem 55:1962-9
Mainz, Emilie R; Wang, Qunzhao; Lawrence, David S et al. (2016) An Integrated Chemical Cytometry Method: Shining a Light on Akt Activity in Single Cells. Angew Chem Int Ed Engl 55:13095-13098
Shell, Thomas A; Lawrence, David S (2015) Vitamin B12: a tunable, long wavelength, light-responsive platform for launching therapeutic agents. Acc Chem Res 48:2866-74
Rodgers, Zachary L; Hughes, Robert M; Doherty, Laura M et al. (2015) B(12)-mediated, long wavelength photopolymerization of hydrogels. J Am Chem Soc 137:3372-8
Priestman, Melanie A; Wang, Qunzhao; Jernigan, Finith E et al. (2015) Multicolor monitoring of the proteasome's catalytic signature. ACS Chem Biol 10:433-40
Shell, Thomas A; Shell, Jennifer R; Rodgers, Zachary L et al. (2014) Tunable visible and near-IR photoactivation of light-responsive compounds by using fluorophores as light-capturing antennas. Angew Chem Int Ed Engl 53:875-8
Oien, Nathan P; Nguyen, Luong T; Jernigan, Finith E et al. (2014) Long-wavelength fluorescent reporters for monitoring protein kinase activity. Angew Chem Int Ed Engl 53:3975-8
Smith, Weston J; Oien, Nathan P; Hughes, Robert M et al. (2014) Cell-mediated assembly of phototherapeutics. Angew Chem Int Ed Engl 53:10945-8
Jernigan, Finith E; Lawrence, David S (2013) A broad spectrum dark quencher: construction of multiple colour protease and photolytic sensors. Chem Commun (Camb) 49:6728-30
Shell, Jennifer R; Lawrence, David S (2013) Probes of the mitochondrial cAMP-dependent protein kinase. Biochim Biophys Acta 1834:1359-63

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