University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Kevan M. Shokat, PhD

Kevan M. Shokat, PhD

Professor and Chair, Department of Cellular and Molecular Pharmacology, UCSF; Professor, Department of Chemistry, UC Berkeley; Investigator, Howard Hughes Medical Institute

Cancer Center Program Memberships

Experimental Therapeutics | Cancer Genetics

Research Summary

Research in my laboratory is focused on the discovery of new chemical based tools to decipher cellular signaling networks with an emphasis on protein kinases and more recently, GTPases. The analysis of signal transduction pathways has proven challenging using the traditional tools of biochemistry, genetics, and chemistry. Biochemical approaches are often limited in utility because signaling networks span from the cell surface to the control of transcription and translation, confounding reconstitution efforts from purified proteins. Genetic approaches allow specific perturbation of single components in an intact cell or organism, yet are often confounded by the emergent properties of signaling cascades. Chemical and pharmacological approaches enable rapid, reversible, and graded (dose-dependent) inactivation of single components in intact cells or organisms. Unfortunately, highly selective chemical probes (agonists, antagonists, traceable substrates, etc.) of protein kinases are difficult to develop because the 500 protein kinases share highly homologous ATP binding pockets. My laboratory has solved this fundamental problem for the largest family of enzymes in the human genome, protein kinases, by development of a strategy based on a combination of protein engineering and organic synthesis. We have termed this approach chemical genetics.

Education

Reed College (Portland, Oregon), B.A., 1986, Chemistry
UC Berkeley (Berkeley, California), Ph.D., 1991, Organic Chemistry


Professional Experience

  • 1986-1991
    (Advisor: Prof. Peter G. Schultz, UC Berkeley): Design and synthesis of haptens for the generation of catalytic antibodies. Thesis Title: New Routes to Catalytic Antibodies.
  • 1992-1994
    (Advisor: Prof. Christopher C. Goodnow, Stanford University): Investigation of mechanisms of immune self-tolerance in transgenic mice.
  • 1994-1998
    Assistant Professor of Chemistry and Molecular Biology, Princeton University
  • 1998-1999
    Associate Professor of Chemistry and Molecular Biology, Princeton University
  • 1999-2002
    Associate Professor of Cellular and Molecular Pharmacology, University of California, San Francisco
  • 1999-2002
    Associate Professor of Chemistry, University of California, Berkeley
  • 2001-present
    Professor of Cellular and Molecular Pharmacology, University of California, San Francisco
  • 2002-present
    Professor of Chemistry, University of California, Berkeley
  • 2004-present
    Vice-Chairman of Cellular and Molecular Pharmacology, UCSF
  • 2004-present
    Investigator, Howard Hughes Medical Institute

Honors & Awards

  • 1986
    Phi Beta Kappa - Reed College
  • 1986-1987
    UC Berkeley Regents Fellowship
  • 1989-1990
    UC Berkeley University Fellowship
  • 1992-1994
    Life Sciences Research Foundation Postdoctoral Fellow
  • 1995-1997
    NSF Early Career Development Award
  • 1996-2000
    Pew Scholar in the Biomedical Sciences
  • 1997-1998
    Glaxo-Wellcome Scholar in Organic Chemistry
  • 1997-2000
    Searle Scholar
  • 1997-2000
    Cottrell Scholar
  • 1999-2001
    Alfred P. Sloan Research Fellow
  • 2001
    Protein Society Young Investigator Award
  • 2002
    Eli Lilly Award in Biological Chemistry

Selected Publications

  1. Rutaganira FU, Barks J, Dhason MS, Wang Q, Lopez MS, Long S, Radke JB, Jones NG, Maddirala AR, Janetka JW, El Bakkouri M, Hui R, Shokat KM, Sibley LD. Inhibition of calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii. J Med Chem. 2017 Sep 21.
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  2. Morisot N, Novotny CJ, Shokat KM, Ron D. A new generation of mTORC1 inhibitor attenuates alcohol intake and reward in mice. Addict Biol. 2017 Jul 06.
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  3. Dang CV, Reddy EP, Shokat KM, Soucek L. Drugging the 'undruggable' cancer targets. Nat Rev Cancer. 2017 Aug; 17(8):502-508.
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  4. Plenker D, Riedel M, Brägelmann J, Dammert MA, Chauhan R, Knowles PP, Lorenz C, Keul M, Bührmann M, Pagel O, Tischler V, Scheel AH, Schütte D, Song Y, Stark J, Mrugalla F, Alber Y, Richters A, Engel J, Leenders F, Heuckmann JM, Wolf J, Diebold J, Pall G, Peifer M, Aerts M, Gevaert K, Zahedi RP, Buettner R, Shokat KM, McDonald NQ, Kast SM, Gautschi O, Thomas RK, Sos ML. Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med. 2017 Jun 14; 9(394).
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  5. Hoppmann C, Wong A, Yang B, Li S, Hunter T, Shokat KM, Wang L. Site-specific incorporation of phosphotyrosine using an expanded genetic code. Nat Chem Biol. 2017 Aug; 13(8):842-844.
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  6. Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight ZA, Shokat KM, Fruman DA. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J Clin Invest. 2017 Jun 01; 127(6):2438.
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  7. Orr AL, Rutaganira FU, de Roulet D, Huang EJ, Hertz NT, Shokat KM, Nakamura K. Long-term oral kinetin does not protect against a-synuclein-induced neurodegeneration in rodent models of Parkinson's disease. Neurochem Int. 2017 Apr 20.
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  8. Fan Q, Aksoy O, Wong RA, Ilkhanizadeh S, Novotny CJ, Gustafson WC, Truong AY, Cayanan G, Simonds EF, Haas-Kogan D, Phillips JJ, Nicolaides T, Okaniwa M, Shokat KM, Weiss WA. A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell. 2017 Mar 13; 31(3):424-435.
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  9. Reed DE, Shokat KM. INPP4B and PTEN Loss Leads to PI-3,4-P2 Accumulation and Inhibition of PI3K in TNBC. Mol Cancer Res. 2017 Jun; 15(6):765-775.
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  10. Urisman A, Levin RS, Gordan JD, Webber JT, Hernandez H, Ishihama Y, Shokat KM, Burlingame AL. An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases. Mol Cell Proteomics. 2017 Feb; 16(2):265-277.
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  11. Uchida Y, Rutaganira FU, Jullié D, Shokat KM, von Zastrow M. Endosomal Phosphatidylinositol 3-Kinase Is Essential for Canonical GPCR Signaling. Mol Pharmacol. 2017 Jan; 91(1):65-73.
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  12. Lazarus MB, Levin RS, Shokat KM. Discovery of new substrates of the elongation factor-2 kinase suggests a broader role in the cellular nutrient response. Cell Signal. 2017 Jan; 29:78-83.
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  13. Novotny CJ, Pollari S, Park JH, Lemmon MA, Shen W, Shokat KM. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nat Chem Biol. 2016 Nov; 12(11):923-930.
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  14. Kostic M, Crews CM, Hertweck C, Shokat K, Suga H. From Powerful Review Articles to Research Breakthroughs. Cell Chem Biol. 2016 Aug 18; 23(8):883-4.
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  15. Jo A, Choi TG, Jo YH, Jyothi KR, Nguyen MN, Kim JH, Lim S, Shahid M, Akter S, Lee S, Lee KH, Kim W, Cho H, Lee J, Shokat KM, Yoon KS, Kang I, Ha J, Kim SS. Inhibition of Carbonyl Reductase 1 Safely Improves the Efficacy of Doxorubicin in Breast Cancer Treatment. Antioxid Redox Signal. 2017 Jan 10; 26(2):70-83.
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  16. Levin RS, Hertz NT, Burlingame AL, Shokat KM, Mukherjee S. Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen. Proc Natl Acad Sci U S A. 2016 Aug 16; 113(33):E4776-83.
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  17. Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016 11; 15(11):771-785.
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  18. Miller RE, Brough R, Bajrami I, Williamson CT, McDade S, Campbell J, Kigozi A, Rafiq R, Pemberton H, Natrajan R, Joel J, Astley H, Mahoney C, Moore JD, Torrance C, Gordan JD, Webber JT, Levin RS, Shokat KM, Bandyopadhyay S, Lord CJ, Ashworth A. Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib. Mol Cancer Ther. 2016 Jul; 15(7):1472-84.
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  19. Saha SK, Gordan JD, Kleinstiver BP, Vu P, Najem MS, Yeo JC, Shi L, Kato Y, Levin RS, Webber JT, Damon LJ, Egan RK, Greninger P, McDermott U, Garnett MJ, Jenkins RL, Rieger-Christ KM, Sullivan TB, Hezel AF, Liss AS, Mizukami Y, Goyal L, Ferrone CR, Zhu AX, Joung JK, Shokat KM, Benes CH, Bardeesy N. Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma. Cancer Discov. 2016 Jul; 6(7):727-39.
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  20. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, Won H, Wong W, Berger M, de Stanchina E, Barratt DG, Cosulich S, Klinowska T, Rosen N, Shokat KM. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016 06 09; 534(7606):272-6.
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