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).

Enzyme Sensors:
We’ve 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’ve 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.

Chemical Genomics:
We’ve assembled a library of 450 FDA-approved drugs to explore a number of biomedically relevant issues. For example, ataxia telangiectasia is a rare childhood disorder characterized by the eventual loss of motor control, moderate to severe immunodeficiency, premature aging, and a pronounced predisposition to cancer. Like many rare childhood diseases, these devastating symptoms are a consequence of genetic mutations that result in the absence, rather than the overabundance, of a key protein. We’ve discovered a unique combination of existing drugs that can be used to generate active proteins even though the genetic blueprint is defective. J. Amer. Chem. Soc., 2004, 126, 5660-1.