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Luke Lairson, Ph.D.

Assistant Professor
(Tenure-Track)
Department of Chemistry
California Campus
Laboratory Website
Scripps VIVO Scientific Profile
llairson@scripps.edu
(858) 784-9335

Scripps Research Joint Appointments

Department of Molecular Medicine
Faculty, Graduate Program

Other Joint Appointments

Molecular Medicine

Research Focus

      My research laboratory uses a chemical biology approach to study cell fate- and cell state-determining processes that play a causative role in the progression of human disease. We have ongoing research programs in areas ranging from the selective induction of endogenous stem cell differentiation to the modulation of immunological response within tumor microenvironments (1). The majority of our research projects involve the use of prospectively isolated primary patient-derived human or engineered rodent cell types, which are used to mimic disease-related process in miniaturized formats. Using the tools of structural diversity and high throughput phenotype-based discovery, typically involving high content imaging or high throughput flow cytometry, small molecules are identified that selectively induce a desired impact on cell fate (e.g., induced differentiation towards a defined lineage) or cell state (e.g., immune checkpoint protein display in response to tumor microenvironment). Validated hit compounds, demonstrated to function via a novel mechanism, are subjected to parallel structure-activity relationship studies and medicinal chemistry-based optimization, as well as target identification and mechanism of action studies. Optimized molecules, possessing suitable pharmacokinetic and target engagement properties, are evaluated in relevant rodent models of disease to assess the relevance of identified mechanisms to disease state. Potential molecular targets are identified using diverse mass spectrometry-based proteomics approaches involving synthesized photo-activatable affinity probe reagents. Downstream mechanism(s) of action are elucidated using standard cell and molecular biology-based techniques. Our research efforts ultimately result in chemistry-based discovery of novel biological mechanisms and the direct enablement of new drug discovery programs.

Education

Ph.D., Chemistry , University of British Columbia, 2007

Professional Experience

2010-2011 Principal Investigator, Genomics Institute of the Novartis Research Foundation
2011-2017 Assistant Professor (Research-Track), Department of Chemistry, The Scripps Research Institute
2012-2017 Principal Investigator, California Institute for Biomedical Research
2016-2017 Director, High Throughput Discovery, California Institute for Biomedical Research

Awards & Professional Activities

Selected References

All Publications

Bollong M.J., Yang B., Vergani N., Beyer B.A., Chin E.N., Zambaldo C., Wang D., Chatterjee A.K., Lairson, L.L.*, Schultz P.G.* (2017) Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis. Proceedings of the National Academy of Science USAIn Press.      * co-corresponding author

Mullarky, E., Lucki, N., Beheshti Zavareh, R., Anglin, J., Gomes, A.P., Nicolay, N.G., Wong, J.C.Y, Christen, S., Takahashi, H., Singh, P.K., Blenisa, J., Warren, D., Fend, S.M., Asarai, J.M., DeNicola, G.M., Lyssiotis, C.A., Lairson, L.L.* and Cantley, L.C.* (2016) Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proceedings of the National Academy of Science USA113: 1778-83.      * co-corresponding author

Bollong M.J., Yun H., Sherwood L., Woods A.K., Lairson L.L.*, Schultz P.G.* (2015) A Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer.  ACS Chemical Biology10: 2193-2198.      * co-corresponding author

Vishal A. Deshmukh, Virginie Tardif, Costas A. Lyssiotis, Chelsea C. Green, Bilal Kerman, Hyung Joon Kim, Krishnan Padmanabhan, Jonathan G. Swoboda, Insha Ahmad, Toru Kondo, Fred H. Gage, Argyrios N. Theofilopoulos, Brian R. Lawson, Peter G. Schultz & Luke L. Lairson.  (2013) A regenerative approach to the treatment of multiple sclerosis.  Nature 502:  327-332.

Luke L. Lairson, Costas A. Lyssiotis, Shoutian Zhu, and Peter G. Schultz.  (2013) Small Molecule Based Approaches to Adult Stem Cell Therapies.  Annual Review of Pharmacology and Toxicology53: 107-125.

Lyssiotis, C.A., Foreman, R.K., Staerk, J., Garcia, M., Mathur, D., Markoulaki, S., Hanna, J., Lairson, L.L., Charette, B.D., Bouchez, L.C., Bollong, M., Kunick, C., Brinker, A., Cho, C.Y., Schultz, P.G., and Jaenisch, R.  (2009)  Reprogramming murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.  Proceedings of the National Academy of Science USA.106: 8912-8917.

Lairson, L.L., Henrissat, B., Davies, G.J., and Withers, S.G.  (2008)  Glycosyltransferases: Structures, Functions, and Mechanisms.  Annual Review of Biochemistry. 77: 521-555.

Lairson, L.L., Watts, A.G., Wakarchuk, W.W., and Withers, S.G.  (2006)  Using Substrate Engineering to Harness Enzyme Promiscuity and Expand Biological Catalysis.  Nature Chemical Biology2: 724-728.   

Lairson, L.L., Chiu, C.P.C., Ly, H.D., He, S., Wakarchuk, W.W., Strynadka, N.C.J., Withers, S.G. (2004)  Intermediate trapping on a mutant retaining alpha-galactosyltransferase identifies an unexpected aspartate residue.  Journal of Biological Chemistry.279: 28339-28344.

Chiu, C.P.C., Watts, A.G., Lairson, L.L., Gilbert, M., Lim, D., Wakarchuk, W.W., Withers, S.G., Strynadka, N.C.J.  (2004)  Structural analysis of the sialyltransferaseCstII from Campylobacter jejuni in complex with a substrate analog.  Nature Structural and Molecular Biology.11: 163-170.