Download BIOGRAPHICAL SKETCH NAME: David S. Lawrence eRA

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
BIOGRAPHICAL SKETCH
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NAME: David S. Lawrence
eRA COMMONS USER NAME (credential, e.g., agency login): dlawrenc
POSITION TITLE: Fred Eshelman Distinguished Professor, Professor of Chemistry, Medicine, and Pharmacy
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION
University of California at Irvine
University of California at Los Angeles
University of Chicago/Rockefeller University
DEGREE
(if
applicable)
Completion
Date
MM/YYYY
BS
06/1976
Biological Sciences
PhD
01/1982
Organic Synthesis
Postdoc
1985
FIELD OF STUDY
Bioorganic Chemistry
A. Personal Statement
The Lawrence research program is multifaceted; encompassing the fields of organic and peptide synthesis,
photochemistry, enzymology, cell and molecular biology, and microscopy. The research group’s expertise lies
in the design, synthesis, characterization, and application of light-responsive agents, including sensors,
inhibitors, activators, proteins, gene-expression, and drug delivery systems. The technology developed for the
latter, in particular, is notable since drug photo-release is easily tuned to any wavelength in the visible and near
IR, enabling multiple drugs to be either simultaneously or sequentially discharged from cell-based carriers.
Photoresponsive agents in the Lawrence Lab have been used to probe, perturb, and reengineer biological
systems.
1.
2.
3.
4.
Nguyen L. T., Oien N. P., Allbritton N. L., and Lawrence D. S. “Lipid Pools As Photolabile ‘Protecting
Groups’: Design of Light-Activatable Bioagents” Angew. Chem. Intl. Ed. Engl., 2013, 52, 9936-9.
PMCID: PMC3840492. Designated as a very important paper (VIP).
Shell T. A., Shell J. R., Rodgers Z. L., and Lawrence D. S. “Tunable Visible and Near-IR
Photoactivation of Light-Responsive Compounds by Using Fluorophores as Light-Capturing Antennas”
Angew. Chem. Intl. Ed. Engl., 2014, 53, 875-8. PMID: 24285381. PMCID: PMC4036634. Designated as
a very important paper (VIP).
Smith W. J., Oien N. P., Hughes R. M., Marvin C. M., Rodgers Z. L., Lee J., and Lawrence D. S. “CellMediated Assembly of Phototherapeutics” Angew. Chem. Intl. Ed. Engl., 2014, 53, 10945 - 8. PMCID:
PMC4209249.
Rodgers Z. L., Hughes R. M., Doherty L. M., Shell J. R., Molesky B. P., Brugh A. M., Forbes M. D.,
Moran A. M., and Lawrence D. S. “B12-Mediated, Long Wavelength Photopolymerization of Hydrogels”
J. Amer. Chem. Soc. 2015, 137, 3372 - 8. PMID: 25697508 [PubMed - in process].
B. Positions and Honors
1976 - 1982
1982 - 1985
1985 - 1991
1991 - 1994
1995
1996 - 2007
Graduate Student, UCLA with R. V. Stevens
Postdoctoral Fellow, University of Chicago and Rockefeller University with E. T. Kaiser
Assistant Professor of Chemistry, SUNY at Buffalo
Associate Professor of Chemistry/Medicinal Chemistry, SUNY at Buffalo
Professor of Chemistry, SUNY at Buffalo
Professor of Biochemistry, Albert Einstein College of Medicine; Albert Einstein
Comprehensive Cancer Center
20072011-
Fred Eshelman Distinguished Professor, University of North Carolina; Professor of
Chemical Biology & Medicinal Chemistry (Pharmacy), Chemistry (Arts & Sciences),
and Pharmacology (Medicine); Member, Lineberger Comprehensive Cancer Center
Chair, Chemical Biology & Medicinal Chemistry, UNC Eshelman School of Pharmacy
Scientific Advisory Committee on Cancer Drug Development, American Cancer Society (1996 - 97); Chemical
and Related Sciences Special Emphasis Study Section, National Institutes of Health (1994); Clinical and
Experimental Therapeutics Study Section, The USAMRMC Breast Cancer Research Program (1997);
Chemical and Related Sciences Special Emphasis Study Section, NIH (1997); International Advisory Board,
The International Conference on Inhibitors of Protein Kinases, Warsaw, Poland (1998); Organizer of the
symposium on “Biosensors: Visualizing the Chemistry of Living Cells”, American Chemical Society Western
Regional Meeting (1999); Biochemistry Study Section, NIH (1999); Bio-Organic and Natural Products
Chemistry Study Section, NIH (2000-04); Samuel M. Rosen Award (2000); Leo M. Davidoff Society (2000);
Olympia Dukakis Award/Grant in A-T Research (2000); Scientific Advisory Board, Keryx Biopharmaceuticals
(2000 - 02), International Advisory Board, The 2nd International Conference on Inhibitors of Protein Kinases,
Warsaw, Poland (2001); Guest Editor, Accounts of Chemical Research Special Issue on Signal Transduction
(2003); International Advisory Board, The 3rd International Conference on Inhibitors of Protein Kinases,
Warsaw, Poland (2003); Scientific Advisory Board, Panomics (2003 - 09); Editorial Advisory Board, Current
Organic Synthesis (2003 - 08); Editorial Advisory Board, Accounts Chemical Research (2004 - present);
Scientific Co-founder, OnSetThera Pharmaceuticals (2004); Member, The Harvey Society (2005 - 07); AAAS
Fellow (2005); Member, American Society for Cell Biology (2006 - 08); Consultant, Sigma-Aldrich (2006 - 07);
International Advisory Board, The 6th International Conference on Inhibitors of Protein Kinases, Warsaw,
Poland (2009); Macromolecular Structure and Function E Study Section, National Institutes of Health (2010
and 2012 - 18); External Reviewer, Department of Medicinal Chemistry, University of Utah (2011); External
Reviewer, Purdue University Cancer Center (2011); International Advisory Board, The 7th International
Conference on Inhibitors of Protein Kinases, Warsaw, Poland (2012); Member, du Vigneaud Award Committee
(2013); Co-Organizer, 23rd American Peptide Symposium and the 6th International Peptide Symposium (2013);
Scientific Founder, Iris BioMed, LLC (2015); American Peptide Society Council (2015 – 2021).
C. Contributions to Science
1. Multicolor Monitoring of Enzyme Action. Conventional strategies for identifying the biochemical basis of
tumorigenesis and metastasis rely upon the search for up- (or down-) regulated genes and proteins. However,
the complexity and heterogeneity of many forms of cancer make it clear that this approach alone is not
sufficient for extracting the information necessary to generate diagnostic and prognostic biomarkers. This
biomedical imperative dictates the development of a series of new cellular and molecular strategies to tackle,
what is admittedly, a devilishly difficult problem. We’ve developed an array of fluorescent sensors of protein
remodeling enzymes (kinases, phosphatases, demininases, proteases) that furnish robust readouts of catalytic
activity (>100 fold) across the visible spectrum and into the near infrared. Furthermore, these sensors are
photophysically distinct, enabling multiple enzymatic activities to be simultaneously monitored. For example,
we’ve employed multicolor sensing of catalytic activity to identify aberrant tyrosine kinase activity in drug
resistant cells, identified a key protein kinase responsible for promoting the transition from prophase to
metaphase, and demonstrated that the proteasome’s three protease activities constitute a characteristic
“catalytic signature” that varies as a function of species, cell type, and disease. Sensors have been used to
correlate signaling activity with prostate cancer invasiveness, distinguish between signaling activity in the
individual compartments of organelles, monitor allosteric crosstalk between active sites within multi-subunit
complexes, and visualize epigenetic enzymatic activity.
a. Wang Q., Zimmerman E. I., Toutchkine A., Martin T. D., Graves L. M., and Lawrence, D. S.
“Multicolor Monitoring of Dysregulated Protein Kinases in Chronic Myelogenous Leukemia”, ACS
Chemical Biology, 2010, 5, 887 - 95. PMCID: PMC2943031.
b. Wang Q., Priestman M. A., and Lawrence D. S. “Monitoring of Protein Arginine Deiminase Activity by
Using Fluorescence Quenching: Multicolor Visualization of Citrullination” Angew. Chem. Intl. Ed.
Engl. 2013, 52, 2323 – 5. PMCID: PMC3752692.
c. Oien N. P., Nguyen L. T., Jernigan F. E., Priestman M. A., and Lawrence D. S. “Long-Wavelength
Fluorescent Reporters for Monitoring Protein Kinase Activity” Angew. Chem. Intl. Ed. Engl. 2014, 53,
3975 – 8. PMCID: PMC4036623.
d. Priestman M. A., Wang Q., Jernigan F. E., Chowdhury R., Schmidt M., and Lawrence D. S.
“Multicolor Monitoring of the Proteasome's Catalytic Signature” ACS Chem. Biol. 2015, 10, 433 - 40.
PMCID: PMC4340355.
2. Acquisition and Application of Potent and Selective Protein Tyrosine Phosphatase (PTPase)
Inhibitors. In collaboration with Zhong-Yin Zhang, we’ve constructed an array of highly selective inhibitors of
PTPases. We developed a paradigm for inhibitor design that has been replicated by many other research
groups (Puius et al. below has been cited 270 times). We were also the first group to create sub-µM inhibitors
of these enzymes. We demonstrated that an inhibitor of PTP1B serves as an insulin sensitizer, an insulin
mimetic, and an appetite suppressant. We’ve identified inhibitors for other PTPases as well, including YopH,
the essential virulent factor of Yersinia pestis (plague).
a. Puius Y. A., Zhao Y., Sullivan M., Lawrence D. S., Almo S. C., and Zhang Z.-Y. “Identification of a
Second Aryl Phosphate-Binding Site in PTP1B: A Paradigm for Inhibitor Design”. Proc. Natl. Acad.
Sci. USA, 1997, 94: 13420 - 5. PMID: 9391040.
b. Shen K., Keng Y.-F., Wu L., Guo X.-L., Lawrence D. S., and Zhang Z.-Y. "Acquisition of A Specific
and Potent PTP1B Inhibitor from a Novel Combinatorial Library and Screening Procedure" J. Biol.
Chem., 2001, 276, 47311 - 9. PMID: 11584002.
c. Xie L., Lee S.-Y., Andersen J. N., Waters S., Shen K., Guo X.-L., Moller N. P. H., Olefsky J. M.,
Lawrence D. S., and Zhang Z.-Y. “Cellular Effects of Small Molecule PTP1B Inhibitors on Insulin
Signaling” Biochemistry, 2003, 42, 12792 - 804. PMID: 14596593.
d. Morrison C. D., White C., Wang Z., Lee S.-Y., Lawrence D. S., Cefalu W. T., Zhang Z.-Y., and Gettys
T. W. “Increased Hypothalamic PTP1B Contributes to Leptin Resistance with Age”, Endocrinology,
2007, 148, 433 - 40. PMID: 17038557.
3. Probing and Perturbing Intracellular Behavior with Light-Responsive Constructs. We’ve employed a
combination of organic photochemistry, organic and peptide synthesis, protein design, cell biology and
microscopy to control and manipulate dynamic biological phenomena. Our molecular constructs have been
used to identify the “steering wheel” of the cell during chemotaxis, to probe intracellular enzymatic activity
during the stages of cell division, and to reveal the mechanisms of gene transcription in single cells. In the last
decade, the field of optogenetics has received a great deal of attention. The vast majority of studies have used
light responsive proteins appropriated from microorganisms. Unfortunately, protein engineering challenges
have hindered the ready acquisition of optogenetic analogs of endogenous mammalian proteins. Recently, we
developed an optogenetic engineering strategy that is straightforward and potentially applicable to a wide
variety of proteins.
a. Dai Z., Dulyaninova N. G., Kumar S., Bresnick A. R., and Lawrence D. S. “Visual Snapshots of
Intracellular Kinase Activity At The Onset of Mitosis”, Chemistry & Biology, 2007, 14, 1254 - 60.
b. Larson D. R., Fritzsch C., Sun L., Meng X., Condeelis J., Lawrence D. S., and Singer R. H. “Direct
Observation of Frequency Modulated Transcription in Single Cells using Light-Activation” eLife 2013,
2, E00750. PMCID: PMC3780543.
c. Hughes R. M. and Lawrence D. S. “Optogenetic Engineering: Light-Directed Cell Motility” Angew.
Chem. Intl. Ed. Engl. 2014, 53, 10904 - 7. PMCID: PMC4196877.
d. Hughes R. M., Freeman D. J., Lamb K. M., Pollet R. M., Smith W. J., and Lawrence D. S.
“Optogenetic Apoptosis: Light-Triggered Cell Death”, Angewandte Chemie International Edition in
English, 2015, 54, in press. PMCID: in process.
4. The Active Site Specificities of Protein Kinases. We’ve developed library-based strategies that combine
peptide frameworks with non-natural small molecules to create hybrids that perturb, sense, or inhibit signaling
enzyme activity. We discovered that even closely related protein kinases can be distinguished based on active
site activities toward unnatural amino acid residues, an observation that ultimately lead to the acquisition of
highly selective protein kinase inhibitors. This work was performed at a time (the early-to-mid 90s) when
scientists still questioned whether it was possible to develop selective active site-targeted protein kinase
inhibitors. Our studies demonstrated that selective protein kinase inhibitors could be identified and these
findings have, of course, been subsequent validated in a host of clinically relevant studies. Our inhibitory
agents have been used in a variety of applications, including the exploration of the molecular basis of memory
with Roger Tsien (UCSD) and Bob Hawkins (Columbia).
a. Kwon Y. G., Mendelow M., and Lawrence D. S. "The Active Site Substrate Specificity of Protein
Kinase C". J. Biol. Chem. 1994, 269, 4839 - 44.
b. Lee T. R., Niu J., and Lawrence D. S. "The Extraordinary Active Site Substrate Specificity of
pp60c-src: A Multiple Specificity Protein Kinase". J. Biol. Chem., 1995, 270, 5375 - 80.
c. Lev-Ram V., Jiang T., Wood J., Lawrence D. S., and Tsien R. Y. “Synergies and Coincidence
Requirements Between NO, cGMP, and Ca2+ in the Induction of Cerebellar Long-Term Depression”
Neuron, 1997, 18, 1025 - 38.
d. Lee J. H., Nandy S. K., and Lawrence D. S. “A Highly Potent and Selective PKCa Inhibitor
Generated Via Combinatorial Modification of A Peptide Scaffold”, J. Amer. Chem. Soc., 2004, 126,
3394 - 5.
5. Self-Assembling Supramolecular Complexes. Although we no longer work in the area of self-assembly,
our papers from the early 1990s are highly cited and form the basis for many of the studies that are ongoing
today. For example, stimuli-responsive supramolecular complexes are of intense interest in a wide variety of
endeavors (materials science, biomedical devices, etc.). We devised a series of strategies that furnished highly
organized structurally well-defined entities, such as the rotaxane described in Rao et al. (which subsequently
served as a basis for the field of “molecular electronics”) and the porphyrin-cyclodextrin complex in Manka et
al, which is still cited in a wide variety of applications.
a. Manka J. S. and Lawrence D. S. "The Template-Driven Self-Assembly of a Heme-Containing
Supramolecular Complex". J. Amer. Chem. Soc. 1990, 112, 2440 - 2.
b. Rao T. V. S. and Lawrence D. S. "The Template-Driven Self-Assembly of a Threaded-Molecular
Loop". J. Amer. Chem. Soc. 1990, 112, 3614 - 5.
c. Dick D., Rao T. V. S., Sukumaran D., and Lawrence D. S. "Molecular Encapsulation: CyclodextrinBased Analogs of Heme-Containing Proteins", J. Amer. Chem. Soc. 1992, 114, 2664 - 9.
d. Jiang T., Levett M., and Lawrence D. S. "Self-Assembling Supramolecular Complexes", Chemical
Reviews, 1995, 95, 2229 - 60.
Complete List of Published Work in MyBibliography:
http://www.ncbi.nlm.nih.gov/sites/myncbi/david.lawrence.1/bibliography/41144279/public/?sort=date&direction=
ascending
D. Research Support
ACTIVE
2RO1CA079954-15
07/01/99 – 11/30/16
1.92 Cal
NCI (PI: Lawrence)
Synthetic Regulators of Tyrosine Protein Kinases
This research program seeks to address the following question: Is it possible to identify and image
subcellular structures that are barometers of metastatic disease in general and the deadly androgenindependent form of prostate cancer in particular? Specific Aims include: (1) Construction of spatiotemporal
probes of Src kinase activity, (2) spatially-resolved imaging of intracellular Src kinase activity, and (3)
assessment of Src kinase activity in invadopodia and the relationship to metastatic potential.
1RO1CA159189-04
06/01/11 – 04/30/16
1.8 Cal
NCI (PI: Lawrence)
Spatiotemporal Control of Tumor Cell Signaling
This project aims to (1) construct profluorescent protein kinases, (2) construct a light-responsive cofilin to
assess the spatial role of cofilin in directed migration, and (3) employ the profluorescent protein kinases to
examine the influence of upstream regulators of cofilin on directed migration. Elucidation of the underlying
mechanisms responsible for invasiveness potential could ultimately serve as the basis for new therapeutic
strategies for the treatment of metastatic disease.
1-15-ACE-21
03/01/15 – 02/28/20
.60 Cal
American Diabetes Association (PI: Gu; co-I: Lawrence)
Lawrence salary support only
Bio-Inspired Synthetic Pathway for Closed-Loop Delivery of Insulin and Glucagon
We will perform two novel strategies to create synthetic insulin vesicles for reversible insulin release upon
fluctuations of blood glucose levels. The first one is based on the fusion of vesicles and the second consists of
polymeric vesicles comprised of a well-organized bilayer, self-assembled by the ultra-acidic-sensitive
amphiphilic copolymer.
1R21NS093617-01
8/01/2015-7/31/2017
1.2 Cal
NIH/NINDS (PI: Lawrence)
Optogenetic Mitochondria-Directed Proteins
The Lawrence lab has developed a potentially general method for creating genetically encoded lightresponsive proteins. This project explores the generality of this method by (1) developing a series of lightresponsive proteins that modulate mitochondrial dynamics and (2) exploring the role of these proteins in
rescuing or contributing to mitochondrial defects found in several neurological disorders.
4DR31505
8/01/2015-7/31/2016
NC TraCS 4D (PI: Lawrence; co-I: Tarrant)
A New Technology for the Targeted Delivery of Anti-Inflammatory Agents
The proposed research program will examine the application of wavelength-encoded B12-drug
phototherapeutics in rheumatoid arthritis (RA) animal models. The collaborative arrangement between the
Lawrence and Tarrant labs is new and could potentially prove to be transformative in the self-management of
RA in particular and rheumatologic diseases in general. In addition, the proposed research program is the first
foray into photodynamic therapy at UNC.
634222
7/01/2015-6/30/2017
UNC Lineberger Comprehensive Cancer Center (PI: Lawrence; co-I: Dayton)
Photochemotherapy
We’ve developed (Lawrence Lab) a new technology that can transform virtually any drug into a
phototherapeutic while providing the means to assign specific wavelengths for the release of specific drugs
from a carrier. Furthermore, we’ve developed (Dayton Lab) a new technology (Acoustic Angiography) for
imaging blood flow, microvasculature, and molecular markers using ultrasound and microbubble contrast
agents. The proposed research program seeks to combine these state-of-the-art drug delivery and imaging
technologies to reengineer and subsequently image the tumor neovasculature as it is remodeled for
therapeutic purposes. Erythrocytes will be used as the carrier for delivering vascular modulating agents, since
red blood cells are biocompatible and enjoy a long circulation lifetime.
PENDING
1R01CA203032-01
9/01/15 – 8/31/20
2.4 Cal
NCI (PI: Lawrence, co-Is: Allbritton, Carey, and Gallagher); scored: 6%
Single Cell Sampling of Signaling Activity in Triple Negative Breast Cancer
We seek to develop a new technology to detect the aberrant biochemistry at the single cell level in tissue from
triple negative breast cancer patients, which could establish the basis for designing unique drug cocktails in a
patient-personalized fashion.
N/A
10/01/2015 – 9/30/2018 0.6 Cal
Eshelman Institute for Innovation (PI: Lawrence; co-I: Hingtgen)
$250,000
Light-Triggered Launching of Anti-Glioblastoma Therapeutics from Cellular Silos
This work seeks to develop therapeutic neural stem cells for the treatment of glioblastoma, identify optimized
parameters for efficient drug delivery using a 3D cell culture system, and perform an in vivo assessment of
efficacy.
1R01NS096838
4/01/16 – 3/30/20
2.4 Cal
NIH/NINDS (PI: Lawrence; co-I: Hingtgen)
Neural Stem Cell Delivery of Therapeutics for the Treatment of Neuropathologies
Stem cell-based therapies have gained acceptance as potentially powerful treatment options for a variety of
previously incurable diseases. However, the controlled release of therapeutics from cell-based delivery
vehicles (stem cells, erythrocytes, macrophages, etc.) is a significant challenge. We will explore the
preparation and properties of neural stem cell-conveyed phototherapeutics and the wavelength-programmed
release of drugs (1) in well-defined 2D co-cultures with target cells, (2) to target cells in 3D culture, and (3) to
diseased sites in animal models.