Benjamin Cravatt, PhD
Scripps Research Joint Appointments
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.
Education
Ph.D. (Macromolecular and Cellular Structure and Chemistry), Scripps Research, 1996B.A. (History), Stanford University, 1992
B.S. (Biological Sciences), Stanford University, 1992
Professional Experience
2017-2018 Co-Chair, Molecular Medicine, Scripps Research2007-2017 Chairman, Chemical Physiology, Scripps Research
2007-2017 Professor, Chemical Physiology, Scripps Research
2004-2012 Professor, Chemistry, Scripps Research
2002-2010 Director, Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute
2004-2007 Professor, Cell Biology, Scripps Research
2001-2004 Associate Professor (with tenure), Cell Biology, Scripps Research
2001-2004 Associate Professor (with tenure), Chemistry, Scripps Research
2000-2001 Assistant Professor, Chemistry, Scripps Research
1996-2001 Assistant Professor, Cell Biology, Scripps Research
Awards & Professional Activities
2020 AACR Award for Outstanding Achievement in Chemistry in Cancer Research
2019 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 References
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. Nat. Chem., 2019, 11, 1113-1123
Zhang, X., Crowley, V.M., Wucherpfennig, T.G., Dix, M.M., Cravatt, B.F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 2019, 15, 737-746.
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. Nat. Chem., 2017, 9, 1181-1190.
Ogasawara, D., Aki-Ichu, T., Vartabedian, V., Benthuysen, J., Reed, A., Ulanovskaya, O., Hulce, J.J., Roberts, A., Brown, S., Rosen, H., Teijaro, J.R., Cravatt, B.F. Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nat Chem. Biol., 2018, 14, 1099-1108.
Bar-Peled, L., Kemper, E.K., Suciu, R.M., Vinogradova, E.V., Backus, K.M., Horning, B.D., Paul, T.A., Ichu, T.A., 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.
Parker, C.P., Galmozzi, A., Wang, Y, Correiar, B.E., Sasaki, K., Joslyn, C.M., Kim, A.S., Cavallaro, C.L., Lawrence, 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.
Backus, K.M., Correia, B.E., Lum, K.M., Forli, S., Horning, B.D., González-Páez, G.E., Chatterjee, S., Lanning, B.R., Teijaro, J.R., Olson, A.J., Wolan, D.W., Cravatt, B.F. Proteome-wide covalent ligand discovery in native biological systems. Nature, 2016, 534, 570-574.
Niphakis, M.J., Lum, K.M., Cognetta, A.B., Correia, B.E., Ichu, T.A., Olucha, J., Brown, S.J., Kundu, S., Piscitelli, F., Rosen, H., Cravatt, B.F. A global map of lipid-binding proteins and their ligandability in cells. Cell, 2015, 161, 1668-1680.
Lanning, B.R., Whitby, L.R., Dix, M.M., Douhan, J., Gilbert, A.M., Hett, E.C., Johnson, T.O., Joslyn, C., Kath, J.C., Niessen, S., Roberts, L.R., Schnute, M.E., Wang, C., Hulce, J.J., Wei, B., Whiteley, L.O., Hayward, M.M., Cravatt, B.F. A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors. Nat Chem Biol., 2014, 10, 760-767.
Moellering, R.E., Cravatt, B.F. Functional lysine modification by an intrinsically reactive primary glycolytic metabolite. Science, 2013, 341, 549-603.
Dix, M.M., Simon, G.M., Wang, C., Okerberg, E., Patricelli, M.P., Cravatt, B.F. Functional interplay between caspase cleavage and phosphorylation sculpts the apoptotic proteome. Cell, 2012, 150, 426-440.
Nomura, D.K., Morrison, B.E., Blankman, J.L., Long, J.Z., Kinsey, S.G., Marcondes, M.C., Ward, A.M., Hahn, Y.K., Lichtman, A.H., Conti, B., Cravatt, B.F. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science, 2011, 334, 809-813.
Weerapana E*, Wang C*, Simon GM, Richter F, Khare S, Dillon MB, Bachovchin DA, Mowen K, Baker D, Cravatt BF. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature, 2010, 468, 790-795.
Schlosburg JE*, Blankman JL*, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, Thomas EA, Selley DE, Sim-Selley LJ, Liu QS, Lichtman AH, Cravatt BF. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat. Neurosci., 2010, 13, 1113-1119.
Nomura DK, Long JZ, Niessen S, Hoover HS, Ng S, Cravatt BF. Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis. Cell, 2010, 140, 49-61.
Bachovchin DA, Brown SJ, Rosen H, Cravatt BF. Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes. Nat. Biotechnol., 2009, 27, 387-394.
Long JZ, Li W, Booker L, Burston JJ, Kinsey SH, Schlosburg JE, Pavon FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat. Chem. Biol., 2009, 5, 37-44.
Dix MM*, Simon GM*, Cravatt BF. Global mapping of the topography and magnitude of proteolytic events in apoptosis. Cell, 2008, 134, 679-91.
Weerapana E, Simon GM, Cravatt BF. Disparate proteome reactivity profiles of carbon electrophiles. Nat. Chem. Biol, 2008, 4, 405-407.
Evans MJ, Saghatelian A, Sorensen EJ, Cravatt BF. Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Nat. Biotechnol., 2005, 23, 1303-1307.
Jessani N, Niessen S, Wei BQ, Nicolau M, Humphrey M, Ji Y, Han W, Noh DY, Yates JR 3rd, Jeffrey SS, Cravatt BF. A streamlined platform for high-content functional proteomics of primary human specimens. Nat Methods., 2005, 2, 691-697.
Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, and Cravatt BF. Assignment of endogenoussubstrates to enzymes by global metabolite profiling. Biochemistry, 2004, 43,14332-14339.
Speers AE, Adam GC, Cravatt BF. Activity-based protein profiling in vivo using a copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. J. Am. Chem. Soc., 2003,125, 4686-4687.
Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science, 2002, 298, 1793-1796.
Liu Y, Patricelli MP, Cravatt BF. Activity-based protein profiling: The serine hydrolases. Proc. Natl. Acad. Sci. USA, 1999, 96, 14694-14699.
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature, 1996, 384, 83-87.