Dysresgulated metabolic pathways contribute to several diseases, including cancer. The discovery and functional characterization of biochemical pathways that support cancer have, however, been hindered by a lack of technologies that can broadly profile metabolites, enzymes, and metabolite- protein interactions in native biological systems. We have addressed this central problem through the development and application of an innovative set of chemical proteomic and metabolomic technologies. In this competitive renewal application, we propose to use and expand our chemical proteomic and metabolomic methods towards the two major goals of: 1) characterizing metabolic (de)methylation pathways that support the growth and malignant properties of cancer cells, and 2) globally mapping and characterizing metabolite-protein interactions that support the growth and malignant properties of cancer cells. These studies are designed to test three major hypotheses: 1) dysregulated metabolic enzymes coordinately control the methylation potential, epigenetic state, and pro-tumorigenic properties of cancer cells, 2) photoreactive, clickable probes offer a general chemoproteomic strategy to map metabolite-protein interactions in living cells, and 3) mapping the full complement of proteins that bind to bioactive sterols and lipids in tumor cells will uncover new biochemical nodes of regulation and crosstalk that define metabolic dependencies of cancers. The ultimate goal of this application is to identify and functionally characterize metabolic pathways that are dysregulated in cancer and support tumorigenesis. The molecular components of these pathways may, in turn, represent new biomarkers and drug targets for the diagnosis and treatment of cancer. The research tools and methods advanced in this proposal should also prove of general value for characterizing biochemical networks in a wide range of physiological and disease processes.

Public Health Relevance

Cancer cells depend on specialized metabolic and signaling pathways for viability and malignancy. The goal of this application is to develop and apply innovative technologies to discover metabolic pathways that are dysregulated in cancer cells and support tumorigenesis. The components of these pathways could in turn serve as new biomarkers and therapeutic targets for the diagnosis and treatment of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Spalholz, Barbara A
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Scripps Research Institute
La Jolla
United States
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Mortenson, David E; Brighty, Gabriel J; Plate, Lars et al. (2018) ""Inverse Drug Discovery"" Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates. J Am Chem Soc 140:200-210
Schonhoft, Joseph D; Monteiro, Cecilia; Plate, Lars et al. (2017) Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients. Sci Transl Med 9:
Hacker, Stephan M; Backus, Keriann M; Lazear, Michael R et al. (2017) Global profiling of lysine reactivity and ligandability in the human proteome. Nat Chem 9:1181-1190
Bar-Peled, Liron; Kemper, Esther K; Suciu, Radu M et al. (2017) Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer. Cell 171:696-709.e23
Parker, Christopher G; Kuttruff, Christian A; Galmozzi, Andrea et al. (2017) Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs. ACS Cent Sci 3:1276-1285
Lum, Kenneth M; Sato, Yoshiaki; Beyer, Brittney A et al. (2017) Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics. ACS Chem Biol 12:2671-2681
Matthews, Megan L; He, Lin; Horning, Benjamin D et al. (2017) Chemoproteomic profiling and discovery of protein electrophiles in human cells. Nat Chem 9:234-243
Parker, Christopher G; Galmozzi, Andrea; Wang, Yujia et al. (2017) Ligand and Target Discovery by Fragment-Based Screening in Human Cells. Cell 168:527-541.e29
Dugan, Amanda; Majmudar, Chinmay Y; Pricer, Rachel et al. (2016) Discovery of Enzymatic Targets of Transcriptional Activators via in Vivo Covalent Chemical Capture. J Am Chem Soc 138:12629-35
Horning, Benjamin D; Suciu, Radu M; Ghadiri, Darian A et al. (2016) Chemical Proteomic Profiling of Human Methyltransferases. J Am Chem Soc 138:13335-13343

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