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

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. Ksionda O, Mues M, Wandler AM, Donker L, Tenhagen M, Jun J, Ducker GS, Matlawska-Wasowska K, Shannon K, Shokat KM, Roose JP. Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy. PLoS One. 2018; 13(5):e0193849.
    View on PubMed
  2. Chorba JS, Galvan AM, Shokat KM. Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype. J Biol Chem. 2018 May 04; 293(18):6692.
    View on PubMed
  3. Hu Q, Shokat KM. Disease-Causing Mutations in the G Protein Gas Subvert the Roles of GDP and GTP. Cell. 2018 Apr 01.
    View on PubMed
  4. Nnadi CI, Jenkins ML, Gentile DR, Bateman LA, Zaidman D, Balius TE, Nomura DK, Burke JE, Shokat KM, London N. Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange. J Chem Inf Model. 2018 Feb 26; 58(2):464-471.
    View on PubMed
  5. Chorba JS, Galvan AM, Shokat KM. Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype. J Biol Chem. 2018 Feb 09; 293(6):1875-1886.
    View on PubMed
  6. Gentile DR, Rathinaswamy MK, Jenkins ML, Moss SM, Siempelkamp BD, Renslo AR, Burke JE, Shokat KM. Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States. Cell Chem Biol. 2017 Dec 21; 24(12):1455-1466.e14.
    View on PubMed
  7. 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 Dec 28; 60(24):9976-9989.
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  8. Morisot N, Novotny CJ, Shokat KM, Ron D. A new generation of mTORC1 inhibitor attenuates alcohol intake and reward in mice. Addict Biol. 2018 Mar; 23(2):713-722.
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  9. Dang CV, Reddy EP, Shokat KM, Soucek L. Drugging the 'undruggable' cancer targets. Nat Rev Cancer. 2017 08; 17(8):502-508.
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  10. Novotny CJ, Hamilton GL, McCormick F, Shokat KM. Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K-Ras. ACS Chem Biol. 2017 Jul 21; 12(7):1956-1962.
    View on PubMed
  11. McGregor LM, Jenkins ML, Kerwin C, Burke JE, Shokat KM. Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes. Biochemistry. 2017 06 27; 56(25):3178-3183.
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  12. 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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  13. 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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  14. 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 06 01; 127(6):2438.
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  15. Liu KH, Niu Y, Konishi M, Wu Y, Du H, Sun Chung H, Li L, Boudsocq M, McCormack M, Maekawa S, Ishida T, Zhang C, Shokat K, Yanagisawa S, Sheen J. Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks. Nature. 2017 05 18; 545(7654):311-316.
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  16. 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 Oct; 109:106-116.
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  17. 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 03 13; 31(3):424-435.
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  18. 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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  19. 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 02; 16(2):265-277.
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  20. 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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