Luke Lairson, PhD

Professor

Department of Chemistry

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

Professional Experience

Awards & Professional Activities

Select Publications

Lucki, N. C.; Villa, G. R.; Vergani, N.; Bollong, Michael J.; Beyer, Brittney A.; Lee, J. W.; Anglin, J. L.; Spangenberg, Stephan H.; Chin, E. N.; Sharma, A.; Johnson, K.; Sander, Philipp N.; Gordon, P.; Skirboll, S. L.; Wurdak, H.; Schultz, Peter G.; Mischel, P. S.; Lairson, Luke 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, Brittney A.; Fang, M.; Sadrian, B.; Montenegro-Burke, J. R.; Plaisted, W. C.; Kok, B. P.; Saez, Enrique; Kondo, T.; Siuzdak, Gary; Lairson, Luke L. Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nature Chemical Biology 2018, 14, 22-28.
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Bollong, Michael J.; Pietila, M.; Pearson, A. D.; Sarkar, T. R.; Ahmad, Insha; Soundararajan, R.; Lyssiotis, Costas A.; Mani, S. A.; Schultz, Peter G.; Lairson, Luke 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, Kenneth M.; Sato, Yoshiaki; Beyer, Brittney A.; Plaisted, Warren C.; Anglin, Justin L.; Lairson, Luke L L.; Cravatt, Benjamin F. Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics. 2017, 12, 2671-2681.
Zavareh, Reza B.; Spangenberg, Step H.; Woods, Ashley; Martínez-Peña, Francisco; Lairson, Luke L L. HSP90 Inhibition Enhances Cancer Immunotherapy by Modulating the Surface Expression of Multiple Immune Checkpoint Proteins. 2021, 28, 158-168.e5.
Chin, Emily N.; Yu, Chenguang; Vartabedian, Vincent F.; Jia, Ying; Kumar, Manoj; Gamo, Ana M.; Vernier, William; Ali, Sabrina H.; Kissai, Mildred; Lazar, Daniel C.; Nguyen, Nhan; Pereira, Laura E.; Benish, Brent; Woods, Ashley K.; Joseph, Sean B.; Chu, Alan; Johnson, Kristen A.; Sander, Philipp N.; Martínez-Peña, Francisco; Hampton, Eric N.; Young, Travi S.; Wolan, Dennis W.; Chatterjee, Arnab K.; Schultz, Peter G.; Petrassi, H M.; Teijaro, John R.; Lairson, Luke L L. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. 2020, 369, 993-999.

News

Scripps Research’s Skaggs Graduate School awards doctoral degrees to 34th graduating class

Institute News

Video

Regenerative medicine for the treatment of MS | Behind the Bench with Luke Lairson

Multiple sclerosis (MS) is a debilitating autoimmune disease that disrupts the central nervous system, causing symptoms like muscle weakness, cognitive challenges and a gradual loss of function that current treatments cannot fully repair. MS arises when the immune system attacks the myelin sheath, the protective layer insulating neurons. Scripps Research chemistry professor Luke Lairson discusses his research on the body’s natural repair pathways—specifically those that activate endogenous stem cells to restore myelin. His work aims to develop therapies that complement existing therapeutic approaches and halt MS progression.

Chemistry Autoimmune Diseases Behind the Bench multiple sclerosis Neurological Disorders

Video

Regenerative medicine for the treatment of MS: Enhancing repair to prevent progression

Multiple sclerosis (MS) is a debilitating autoimmune disease that disrupts the central nervous system, causing symptoms like muscle weakness, cognitive challenges and a gradual loss of function that current treatments cannot fully repair. MS arises when the immune system attacks the myelin sheath, the protective layer insulating neurons. In this Front Row lecture, Scripps Research chemistry professor Luke Lairson discussed his research on the body’s natural repair pathways—specifically those that activate endogenous stem cells to restore myelin. His work aims to develop therapies that complement existing therapeutic approaches and halt MS progression.

Chemistry Autoimmune Diseases Front Row Lecture Series multiple sclerosis Neurological Disorders

Video

Front Row spotlight with Luke Lairson

Multiple sclerosis (MS) is a debilitating autoimmune disease that disrupts the central nervous system, causing symptoms like muscle weakness, cognitive challenges and a gradual loss of function that current treatments cannot fully repair. MS arises when the immune system attacks the myelin sheath, the protective layer insulating neurons. Scripps Research chemistry professor Luke Lairson will discuss his research on the body’s natural repair pathways—specifically those that activate endogenous stem cells to restore myelin. His work aims to develop therapies that complement existing therapeutic approaches and halt MS progression.

Chemistry Autoimmune Diseases Front Row Lecture Series multiple sclerosis Neurological Disorders

Magazine

Rejuvenating the aging brain

As humans live longer, they’re at increased risk of developing devastating neurodegenerative diseases. At Scripps Research, scientists are closer than ever to understanding how these diseases harm the brain and identifying possible drugs to stop them.

Neuroscience Molecular & Cellular Biology Chemistry

News

Unleashing the immune system’s ‘STING’ against cancer

A small molecule that activates the immune protein STING shows promising results against tumors.

Immunology & Microbiology Calibr-Skaggs

News

Chemistry technique acts as ‘warp drive’ for creating better synthetic molecules for medicine

In a study with implications for the future of drug discovery, Scripps Research scientists showed they were able to turn simple chemicals into unique 3-D structures resembling those found in nature.

News

New screening method identifies potential anticancer compounds that reawaken T cells

Cancerous tumors often thrive because they exhaust the immune system's T cells. The new approach uncovers compounds that can restore the function of these disease-fighting cells.

Michael Oldstone