Fred Eshelmann Distinguished Professor of Pharmacy
Division of Medicinal Chemistry & Natural Products, School of Pharmacy & Deptartment of Chemistry
- Chemical Biology of Signal Transduction
- Signaling Pathway Sensors, Inhibitors, and Activators
- Photocontrolled Reagents for the Spatial and Temporal Manipulation of Cell Signalling
Living cells have been referred to as the test tubes of the 21st century. The design and synthesis of molecules that inhibit, probe, or alter the biochemistry of the cell lies at the nexus of chemistry and biology. The field of Chemical Biology seeks to correlate the underlying chemistry of life with the behavior of cells, tissues, and organisms. By revealing the nature of the molecular engine that drives cellular behavior Chemical Biology provides the molecular foundation upon which innovative therapies can be created for the entire spectrum of human afflictions.
Inhibitors and Drug Development
We have developed a combinatorial library strategy that creates extraordinarily potent and selective inhibitors for specific signaling proteins. Among the later is a protein phosphatase that negatively regulates the insulin (diabetes) and leptin (obesity) signaling pathways (Endocrinology, 2007, 148, 433-40) and members of the Src kinase family implicated in cancer (J. Amer. Chem. Soc. 2006, 128, 5996-7).
We have synthesized fluorescent sensors that furnish a real-time and highly sensitive readout of enzymatic activity in living cells. This allows us to "watch" the chemistry of the cell as the cell responds to environmental stimuli. J. Amer. Chem. Soc., 2007, 129, 2742-3.
Light-Activated Inhibitors, Sensors, and Signaling Proteins
These light sensitive agents can be switched on or off at any time or place inside living cells, thereby allowing us to control the chemistry of the cell wherever and whenever we so desire. Issues currently under study include an assessment of signaling pathways at the various stages of mitosis, during cell motility, and in memory and learning. For example, a light-activated signaling protein has been prepared and used to probe the "steering apparatus" of the cell during motility. Science, 2004, 303, 743-6 and J. Amer. Chem. Soc., 2006, 128, 14016-7.
Light-Induced Gene Expression
We have developed a strategy for using light to activate the expression of any gene of interest. This furnishes a direct means to examine the biological consequences of gene expression within the context of specific tissue microenvironments. This technology is being applied to living animals in collaboration with a group at the Albert Einstein College of Medicine. J. Biomed. Optics 2005, 10, 0514061-9.
Click above for PubMed publications.
- Li, H., Hah, J.M., and Lawrence, D.S. (2008) Light-mediated liberation of enzymatic activity: "small molecule" caged protein equivalents. J Amer Chem Soc 130: 10464-5. Abstract
- Wakata, A., Cahill, S.M., Blumenstein, M., Gunby, R.H., Jockusch, S., Marti, A.A., Cimbro, B., Gambacorti-Passerini, C., Donella-Deanna, A., Pinna, L.A., Turro, N.J., and Lawrence, D.S. (2008) A Mechanistic Design Principle for Protein Tyrosine Kinase Sensors: Application to a Validated Cancer Target. Org Lett 10: 301-4. Abstract
- Garrett, S.C., Turner, N., Rybin, A., Toutchkine, A., Hahn, K.M., Lawrence, D.S., and Bresnick, A.R. (2008) A Biosensor of S100A4 Metastasis Factor Activation – Inhibitor Screening and Cellular Activation Dynamics. Biochemistry 47: 986-96. Abstract
- Sharma, V., Wang, Q., and Lawrence, D.S. (2008) Peptide-based fluorescent sensors of protein kinase activity: Design and applications. Biochim Biophys Acta 1784: 94-9. Abstract
- Lee, J.H., Kumar, S., and Lawrence, D.S. (2008) Stepwise Combinatorial Evolution of Akt Bisubstrate Inhibitors. ChemBioChem 9: 507-9. Abstract
- Almo, S.C., Bonanno, J. B., Sauder J.M., Emtage, S., Dilorenzo, T.P., Malashkevich, V., Wasserman, S.R., Swaminathan, S., Eswaramoorthy, S., Agarwal, R., Kumaran, D., Madegowda, M., Ragumani, S., Patskovsky, Y., Alvarado, J., Ramagopal, U.A., Faber-Barata, J., Chance, M.R., Sali A., Fiser, A., Zhang, Z.Y., Lawrence, D.S., and Burley, S.K. (2007) Structural genomics of protein phosphatases. J Struct Funct Genomics 8: 121-40. Abstract
- Dai, Z., Dulyaninova, N.G., Kumar, S., Besnick, A.R., and Lawrence, D.S. (2007) Visual Snapshots of Intracellular Kinase Activity At The Onset of Mitosis. Chem & Biol 14: 1254-60. Abstract