Source: Interfolio F180
Benjamin Cravatt
Research Focus
Our research group aims to understand the roles that proteins play in human physiological and pathological processes and to use this knowledge to identify novel therapeutic targets and drugs to treat disease. To achieve these goals, we develop and apply new technologies that bridge the fields of chemistry and biology, ascribing to the philosophy that the most significant biomedical problems require creative multidisciplinary approaches for their solution. Our technological innovations address fundamental challenges in human physiology and disease that are beyond the scope of contemporary methods. For instance, enzymes are tightly regulated by post-translational events in vivo, meaning that their activity may not correlate with expression as measured by standard genomic and proteomic approaches. Considering that it is an enzyme's activity, rather than abundance that ultimately dictates its role in cell physiology and pathology, we have introduced a set of proteomic technologies that directly measures this parameter. These activity-based protein profiling (ABPP) methods exploit the power of chemistry to engender new tools and assays for the global analysis of enzyme activities. The enzyme activity profiles generated by ABPP constitute unique molecular portraits of cells and tissues that illuminate how metabolic and signaling networks are regulated in vivo. Additionally, by evaluating enzymes based on functional properties rather than mere abundance, ABPP acquires high-content proteomic information that is enriched in novel markers and targets for the diagnosis and treatment of human disease. We have also shown that ABPP can serve as a near-universal assay for the discovery of small-molecule inhibitors or ligands of proteins directly in native biological systems and, through doing so, greatly expand the scope of proteins that can be targeted by chemical probes and drugs.
We complement these efforts in technology development with focused studies on individual proteins. With particular interests in the nervous system and cancer, we select proteins, such as the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), for detailed investigation using a range of chemical, biochemical, genetic, and pharmacological techniques. This multidisciplinary approach ensures that we generate all of the tools and models required to assign molecular, cellular, and physiological functions to enzymes and, as an important corollary, assess their suitability as therapeutic targets. Notably, these basic discovery projects both benefit from and provide a fertile testing ground for our technological innovations. Thus, through the integration of two complementary research programs, one dedicated to methods development for chemical proteomics, and the other to the characterization of key proteins and pathways, our group achieves a unique balance that cultivates the creation and rapid implementation of cutting-edge technologies for the advancement of basic and translational science.
Links
The Skaggs Institute for Chemical Biology
The Skaggs Institute Scientific Report
Education
B.S. (Biological Sciences), Stanford University, 1992B.A. (History), Stanford University, 1992
Ph.D. (Macromolecular and Cellular Structure and Chemistry), The Scripps Research Institute, 1996
Professional Experience
2018-present Professor, Department of Chemistry, TSRI2007-2017 Professor and Chair, Department of Chemical Physiology, TSRI
2004-2007 Professor, Departments of Cell Biology and Chemistry, TSRI
2004-present Norton B. Gilula Chair in Chemical Biology, TSRI
2002-present Director, Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute
2001-2004 Associate Professor (with tenure), Departments of Cell Biology and Chemistry, TSRI
2000-2001 Assistant Professor, Department of Chemistry, TSRI
1996-2001 Assistant Professor, The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute (TSRI)
Awards & Professional Activities
2020 AACR Award for Outstanding Achievement in Chemistry in Cancer Research2019 Jeremy Knowles Award, Royal Society of Chemistry
2018 R35 Outstanding Investigator Award, National Cancer Institute
2018 Prous Institute-Overton and Meyer Award for New Technologies in Drug Discovery, EFMC
2017 Member, National Academy of Medicine 2017 Robert M. Scarborough Award, Medicinal Chem Div, ACS
2017 ACS Chemical Biology Lectureship, American Chemical Society
2016 Member, American Academy of Arts and Sciences
2015 The Sato Memorial International Award, Pharmaceutical Society of Japan
2014 Member, The National Academy of Sciences
2014 ASBMB-Merck Award
2009-10 Pfizer Fellowship for Creativity in Chemistry and Chemical Biology
2009 MERIT Award, National Cancer Institute
2008 Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry, Elsevier
2007 Irving Sigal Young Investigator Award, The Protein Society
2005 Young Investigator Award, International Cannabinoid Research Society
2004 Eli Lilly Award in Biological Chemistry, American Chemical Society
2002 Promega Award for Early Career Life Scientists, American Society for Cell Biology
2002 Technology Review’s TR100 Top 100 Young Innovators Award
Selected Publications
Wang, Y.; Dix, M. M.; Bianco, G.; Remsberg, J. R.; Lee, H. Y.; Kalocsay, M.; Gygi, S. P.; Forli, S.; Vite, G.; Lawrence, R. M.; Parker, C. G.; Cravatt, B. F. Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs. Nature Chemistry 2019, 11, 1113-1123.
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Zhang, X.; Crowley, V. M.; Wucherpfennig, T. G.; Dix, M. M.; Cravatt, B. F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nature Chemical Biology 2019, 15, 737-746.
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Hacker, S. M.; Backus, K. M.; Lazear, M. R.; Forli, S.; Correia, B. E.; Cravatt, B. F. Global profiling of lysine reactivity and ligandability in the human proteome. Nature Chemistry 2017, 9, 1181-1190.
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Ogasawara, D.; Ichu, T.; Vartabedian, V. F.; Benthuysen, J.; Jing, H.; Reed, A. W.; Ulanovskaya, O. A.; Hulce, J. J.; Roberts, A. J.; Brown, S. D.; Rosen, H.; Teijaro, J. R.; Cravatt, B. F. Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nature Chemical Biology 2018, 14, 1099-1108.
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Bar-Peled, L.; Kemper, E. K.; Suciu, M. R.; Vinogradova, E. V.; Backus, K. M.; Horning, B. D.; Paul, T. A.; Ichu, T.; Svensson, R. U.; Olucha, J.; Chang, M. W.; Kok, B. P.; Zhu, Z.; Ihle, N. T.; Dix, M. M.; Jiang, P.; Hayward, M. M.; Saez, E.; Shaw, R. J.; Cravatt, B. F. Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 2017, 171, 696-709.
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Parker, C. G.; Galmozzi, A.; Wang, Y.; Correia, B. E.; Sasaki, K.; Joslyn, C. M.; Kim, A. S.; Cavallaro, C. L.; Lawrence, R. M.; Johnson, S. R.; Narvaiza, I.; Saez, E.; Cravatt, B. F. Ligand and target discovery by fragment-based screening in human cells. Cell 2017, 168, 527-541.
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