Luke Lairson, PhD
Scripps Research Joint Appointments
Other Joint Appointments
Molecular MedicineResearch 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, 2007B.Sc. (Biochemistry), University of Guelph, 2002
Professional Experience
2017-2019 Assistant Professor, Chemistry, Scripps Research2012-2017 Principal Investigator, California Institute for Biomedical Research (Calibr), Scripps Research
2011-2017 Assistant Professor of Chemistry, Chemistry, Scripps Research
2010-2011 Research Investigator, Genomics Institute of the Novartis Research Foundation (GNF)
2007-2009 CIHR Fellow, Scripps Research
Selected References
Zavareh R.B., Spangenberg S.H., Woods A., Martínez-Peña F., Lairson L.L. (2021)
HSP90 Inhibition Enhances Cancer Immunotherapy by Modulating the Surface Expression of Multiple Immune Checkpoint Proteins. Cell Chemical Biology. S2451-9456(20)30384-6. Online ahead of print.
Chin E.N., Yu C., Vartabedian V.F., Jia Y., Kumar M., Gamo A.M., Vernier W., Ali S.H., Kissai M., Lazar D.C., Nguyen N., Pereira L.E., Benish B., Woods A.K., Joseph S.B., Chu A., Johnson K.A., Sander P.N., Martínez-Peña F., Hampton E.N., Young T.S., Wolan D.W., Chatterjee A.K., Schultz P.G., Petrassi H.M., Teijaro J.R., Lairson, L.L. (2020) Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science. 369: 993-999.
Lucki N.C., Villa G.R., Vergani N., Bollong M.J., Beyer B.A., Lee J.W., Anglin J.L., Spangenberg S.H., Chin E.N., Sharma A., Johnson K., Sander P.N., Gordon P., Skirboll S.L., Wurdak H., Schultz P.G., Mischel P.S., Lairson L.L. (2019)
A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer. Proceedings of the National Academy of Science USA. 116: 6435-6440.
Beyer, B.A., Fang, M., Sadrian, B., Montenegro-Burke, J.R., Plaisted, W., Kok., B.P.C., Saez, E., Kondo, T., Siuzdak, G., Lairson, L.L. (2018) Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nature Chemical Biology. 14: 22-28.
Bollong, M.J., Pietila, M., Pearson, A.D., Sarkar, T. R., Ahmad, I., Soundararajan, R., Lyssiotis, C.A., Mani, S.A., Schultz, P.G., Lairson, L.L. (2017) A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers. Proceedings of the National Academy of Science USA. 14: E9903-E9912.
Lum K.M., Sato Y., Beyer B.A., Plaisted W.C., Anglin J.L., Lairson L.L.*, Cravatt B.F.* (2017) Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics. ACS Chemical Biology. In Press. * co-corresponding author
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 USA. 114: 4679-84. * 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 USA. 113: 1778-83. * 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 Toxicology. 53: 107-125.
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 Biology. 2: 724-728.