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. Lou K, Gilbert LA, Shokat KM. A Bounty of New Challenging Targets in Oncology for Chemical Discovery. Biochemistry. 2019 Jul 25.
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  2. Lou K, Steri V, Ge AY, Hwang YC, Yogodzinski CH, Shkedi AR, Choi ALM, Mitchell DC, Swaney DL, Hann B, Gordan JD, Shokat KM, Gilbert LA. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Sci Signal. 2019 May 28; 12(583).
    View on PubMed
  3. Hernández-Ortega S, Sánchez-Botet A, Quandt E, Masip N, Gasa L, Verde G, Jiménez J, Levin RS, Rutaganira FU, Burlingame AL, Wolfgeher D, Ribeiro MPC, Kron SJ, Shokat KM, Clotet J. Phosphoregulation of the oncogenic protein regulator of cytokinesis 1 (PRC1) by the atypical CDK16/CCNY complex. Exp Mol Med. 2019 Apr 16; 51(4):44.
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  4. Moss SM, Taylor IR, Ruggero D, Gestwicki JE, Shokat KM, Mukherjee S. A Legionella pneumophila Kinase Phosphorylates the Hsp70 Chaperone Family to Inhibit Eukaryotic Protein Synthesis. Cell Host Microbe. 2019 Mar 13; 25(3):454-462.e6.
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  5. Katsuno Y, Meyer DS, Zhang Z, Shokat KM, Akhurst RJ, Miyazono K, Derynck R. Chronic TGF-ß exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition. Sci Signal. 2019 Feb 26; 12(570).
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  6. Wong AW, Urisman A, Burlingame AL, Shokat KM. Chemically reprogramming the phospho-transfer reaction to crosslink protein kinases to their substrates. Protein Sci. 2019 Mar; 28(3):654-662.
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  7. Ocasio CA, Warkentin AA, McIntyre PJ, Barkovich KJ, Vesely C, Spencer J, Shokat KM, Bayliss R. Type II Kinase Inhibitors Targeting Cys-Gatekeeper Kinases Display Orthogonality with Wild Type and Ala/Gly-Gatekeeper Kinases. ACS Chem Biol. 2018 Oct 19; 13(10):2956-2965.
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  8. Barkovich KJ, Moore MK, Hu Q, Shokat KM. Chemical genetic inhibition of DEAD-box proteins using covalent complementarity. Nucleic Acids Res. 2018 Sep 28; 46(17):8689-8699.
    View on PubMed
  9. Chamberlain CE, German MS, Yang K, Wang J, VanBrocklin H, Regan M, Shokat KM, Ducker GS, Kim GE, Hann B, Donner DB, Warren RS, Venook AP, Bergsland EK, Lee D, Wang Y, Nakakura EK. A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors. Mol Cancer Ther. 2018 Dec; 17(12):2702-2709.
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  10. Chorba JS, Galvan AM, Shokat KM. A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9. J Vis Exp. 2018 08 28; (138).
    View on PubMed
  11. Donnella HJ, Webber JT, Levin RS, Camarda R, Momcilovic O, Bayani N, Shah KN, Korkola JE, Shokat KM, Goga A, Gordan JD, Bandyopadhyay S. Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer. Nat Chem Biol. 2018 08; 14(8):768-777.
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  12. 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.
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  13. 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 05 04; 293(18):6692.
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  14. Hu Q, Shokat KM. Disease-Causing Mutations in the G Protein Gas Subvert the Roles of GDP and GTP. Cell. 2018 05 17; 173(5):1254-1264.e11.
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  15. 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 02 26; 58(2):464-471.
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  16. 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 02 09; 293(6):1875-1886.
    View on PubMed
  17. 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 12 21; 24(12):1455-1466.e14.
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  18. 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 12 28; 60(24):9976-9989.
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  19. Morisot N, Novotny CJ, Shokat KM, Ron D. A new generation of mTORC1 inhibitor attenuates alcohol intake and reward in mice. Addict Biol. 2018 03; 23(2):713-722.
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  20. 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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