The long-term objectives of the proposed research program are to elucidate the biological role of tyrosine-specific protein kinases (PTKs) and to explore the biochemical consequences of their deregulation. These enzymes play a crucial, albeit still enigmatic role in the signal transduction pathways responsible for cell growth and differentiation. Upon the loss of key regulatory controls, either through the over-expression or mutation of specific PTKs, the oncogenic potential of these enzymes is unleashed. Regulatory agents, which disturb or otherwise alter the myriad protein-protein recognition events that drive signal transduction pathways, will be extraordinary useful in helping to decipher the role of specific enzymes in these pathways. In addition, these regulatory agents may ultimately provide the foundation upon which therapeutically useful components can be devised. The proposed research aims to develop (1) peptide/non-peptide conjugates directed against the SH2 and SH3 domains of PTKs, based upon our recent acquisition o f high affinity SH2-targeted conjugates; (2) non- phosphorylatable PTK active site-directed ligands based upon our previous observation that the active site specificity of PTKs toward unnatural ligands is surprising variable; (3) bivalent ligands that block both the kinase activity and the intracellular localization of PTKs; (4) photo-compliant modulators of PTK action; and (5) an assessment of the in vivo efficacy of these PTK regulatory agents.
| 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 |
| Shell, Jennifer R; Lawrence, David S (2013) Probes of the mitochondrial cAMP-dependent protein kinase. Biochim Biophys Acta 1834:1359-63 |
| 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 |
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