David Lawrence works to understand the biochemical processes of the cell by studying them as they happen in the cell as opposed to studying them in vitro. He currently focuses on applying his discoveries to cancer detection and treatment and, to a more limited extent, inflammatory diseases. Lawrence is a Fred Eshelman Distinguished Professor of Medicinal Chemistry and holds joint appointments in the Department of Chemistry and the Department of Pharmacology and is a member of the UNC Lineberger Comprehensive Cancer Center. Before joining the School in 2007, Lawrence spent eleven years as a professor of biochemistry at the Albert Einstein College of Medicine at Yeshiva University in New York. Before that, he was at the State University of New York at Buffalo for ten years.
Living cells have been referred to as the test tubes of the 21st century. The creation 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.
The Lawrence research program is multifaceted, encompassing the fields of organic and peptide synthesis, photochemistry, enzymology, molecular and cell biology, and microscopy. This research team is engaged in the synthesis, characterization and cell-based application of light-responsive agents (inhibitors, sensors, activators, proteins and gene expression system), which are designed to manipulate and probe the biochemical pathways that control cell behavior. Disease states under investigation include cancer, disorders of metabolism, and inflammatory diseases.
We have developed a combinatorial library strategy that creates extraordinarily potent and selective inhibitors for specific signaling proteins. Among the later is a phosphatase that negatively regulates the insulin (diabetes) and leptin (obesity) signaling pathways. Methods in Molecular Biology, 2012, 928, 53 – 65.
We’ve constructed 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. Am. Chem. Soc. 2011, 133, 2331 – 3; Angew. Chem. Int. Ed. Engl., 2013, 52, 2323 – 5.
These light sensitive agents can be switched on or off at any time or place inside or outside living cells and thereby furnish control over where and when the bio-reagent is activated. Issues currently under study include an assessment of signaling pathways at the various stages of mitosis, during cell motility, and site-directed drug delivery. Angew. Chem. Int. Ed. Engl.,2012, 51, 7684 -7; Angew. Chem. Int. Ed. Engl., 2013, 52, 9936 – 9;Angew. Chem. Int. Ed. Engl., 2014, 53, 875 -8.
We’ve developed a strategy for activating the expression of any given gene of interest in response to light. 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 eLife,2013, 2: e00750.
The advent of effective pharmacologic kinase inhibitors for clinical applications has created a critical need for enzymatic assays of protein kinases in disease models and in patient samples. Such biochemical analyses of aberrant signaling pathways are now needed to direct the best treatment option as well as to assess treatment efficacy in individual patients. The goal of this collaborative (with Professor Nancy Albritton) interdisciplinary research project is to create the instrumentation and chemical tools needed to directly assess the catalytic activity of protein kinases in living cells. Analyst, 2012, 137, 3028 – 38; Analytical Chemistry,2012, 84, 7195 – 202; PLoS One, 2012, 7, e48867; Analytical Chemistry,2013, 85, 6136 – 42.