Source: Interfolio F180
Luke Lairson
Scripps Research Joint Appointments
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, 2007B.S. (Biochemistry), University of Guelph, 2002
Professional Experience
2010-2011 Principal Investigator, Genomics Institute of the Novartis Research Foundation2011-2017 Assistant Professor 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
2010 Canadian Society for Chemistry Boehringer Ingelheim Thesis Award2007 Royal Society Short Visit Award
2005 Boehringer-Ingelheim Scholarship for Organic Chemistry
1998 Jim Stockman Memorial Scholarship
Selected Publications
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. A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer. Proceedings of the National Academy of Sciences of the United States of America 2019, 116, 6435-6440.
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Beyer, B. A.; Fang, M.; Sadrian, B.; Montenegro-Burke, J. R.; Plaisted, W. C.; Kok, B. P.; Saez, E.; Kondo, T.; Siuzdak, G.; Lairson, L. L. Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nature Chemical Biology 2018, 14, 22-28.
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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. A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers. Proceedings of the National Academy of Sciences of the United States of America 2017, 114, E9903-E9912.
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Lum, K. M.; Sato, Y.; Beyer, B. A.; Plaisted, W. C.; Anglin, J. L.; Lairson, L. L.; Cravatt, B. F. Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics. 2017, 12, 2671-2681.
Zavareh, R. B.; Spangenberg, S. H.; Woods, A.; Martínez-Peña, F.; Lairson, L. L. HSP90 Inhibition Enhances Cancer Immunotherapy by Modulating the Surface Expression of Multiple Immune Checkpoint Proteins. 2021, 28, 158-168.e5.
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. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. 2020, 369, 993-999.