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

Kevan M. Shokat, PhD

Professor, 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

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. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Correa Marrero M, Polacco BJ, Melnyk JE, Ulferts S, Kaake RM, Batra J, Richards AL, Stevenson E, Gordon DE, Rojc A, Obernier K, Fabius JM, Soucheray M, Miorin L, Moreno E, Koh C, Tran QD, Hardy A, Robinot R, Vallet T, Nilsson-Payant BE, Hernandez-Armenta C, Dunham A, Weigang S, Knerr J, Modak M, Quintero D, Zhou Y, Dugourd A, Valdeolivas A, Patil T, Li Q, Hüttenhain R, Cakir M, Muralidharan M, Kim M, Jang G, Tutuncuoglu B, Hiatt J, Guo JZ, Xu J, Bouhaddou S, Mathy CJP, Gaulton A, Manners EJ, Félix E, Shi Y, Goff M, Lim JK, McBride T, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, De Wit E, Leach AR, Kortemme T, Shoichet B, Ott M, Saez-Rodriguez J, tenOever BR, Mullins RD, Fischer ER, Kochs G, Grosse R, García-Sastre A, Vignuzzi M, Johnson JR, Shokat KM, Swaney DL, Beltrao P, Krogan NJ. The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell. 2020 08 06; 182(3):685-712.e19.
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  2. Coles GL, Cristea S, Webber JT, Levin RS, Moss SM, He A, Sangodkar J, Hwang YC, Arand J, Drainas AP, Mooney NA, Demeter J, Spradlin JN, Mauch B, Le V, Shue YT, Ko JH, Lee MC, Kong C, Nomura DK, Ohlmeyer M, Swaney DL, Krogan NJ, Jackson PK, Narla G, Gordan JD, Shokat KM, Sage J. Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells. Cancer Cell. 2020 Jul 13; 38(1):129-143.e7.
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  3. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 07; 583(7816):459-468.
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  4. Fan Q, An Z, Wong RA, Luo X, Lu ED, Baldwin A, Mayekar MK, Haderk F, Shokat KM, Bivona TG, Weiss WA. Betacellulin drives therapy resistance in glioblastoma. Neuro Oncol. 2020 04 15; 22(4):457-469.
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  5. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O'Meara MJ, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Naing ZZC, Zhou Y, Peng S, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Shen W, Shi Y, Zhang Z, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Ramachandran R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Lin Y, Wankowicz SA, Bohn M, Trenker R, Young JM, Cavero D, Hiatt J, Roth T, Rathore U, Subramanian A, Noack J, Hubert M, Roesch F, Vallet T, Meyer B, White KM, Miorin L, Agard D, Emerman M, Ruggero D, García-Sastre A, Jura N, von Zastrow M, Taunton J, Schwartz O, Vignuzzi M, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor S, Fraser JS, Gross J, Sali A, Kortemme T, Beltrao P, Shokat K, Shoichet BK, Krogan NJ. A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing. bioRxiv. 2020 Mar 22.
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  6. Tan X, Banerjee P, Pham EA, Rutaganira FUN, Basu K, Bota-Rabassedas N, Guo HF, Grzeskowiak CL, Liu X, Yu J, Shi L, Peng DH, Rodriguez BL, Zhang J, Zheng V, Duose DY, Solis LM, Mino B, Raso MG, Behrens C, Wistuba II, Scott KL, Smith M, Nguyen K, Lam G, Choong I, Mazumdar A, Hill JL, Gibbons DL, Brown PH, Russell WK, Shokat K, Creighton CJ, Glenn JS, Kurie JM. PI4KIIIß is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma. Sci Transl Med. 2020 01 22; 12(527).
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  7. Guiley KZ, Stevenson JW, Lou K, Barkovich KJ, Kumarasamy V, Wijeratne TU, Bunch KL, Tripathi S, Knudsen ES, Witkiewicz AK, Shokat KM, Rubin SM. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition. Science. 2019 12 13; 366(6471).
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  8. Wong RA, Luo X, Lu M, An Z, Haas-Kogan DA, Phillips JJ, Shokat KM, Weiss WA, Fan QW. Cooperative Blockade of PKCa and JAK2 Drives Apoptosis in Glioblastoma. Cancer Res. 2020 02 15; 80(4):709-718.
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  9. Loonat AA, Martin ED, Sarafraz-Shekary N, Tilgner K, Hertz NT, Levin R, Shokat KM, Burlingame AL, Arabacilar P, Uddin S, Thomas M, Marber MS, Clark JE. p38? MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin. FASEB J. 2019 12; 33(12):13131-13144.
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  10. Zhang Z, Shokat KM. Bifunctional Small-Molecule Ligands of K-Ras Induce Its Association with Immunophilin Proteins. Angew Chem Int Ed Engl. 2019 11 04; 58(45):16314-16319.
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  11. Lou K, Gilbert LA, Shokat KM. A Bounty of New Challenging Targets in Oncology for Chemical Discovery. Biochemistry. 2019 08 06; 58(31):3328-3330.
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  12. 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 05 28; 12(583).
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  13. 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 04 16; 51(4):1-17.
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  14. 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 03 13; 25(3):454-462.e6.
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  15. 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 02 26; 12(570).
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  16. Wong AW, Urisman A, Burlingame AL, Shokat KM. Chemically reprogramming the phospho-transfer reaction to crosslink protein kinases to their substrates. Protein Sci. 2019 03; 28(3):654-662.
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  17. 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 10 19; 13(10):2956-2965.
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  18. Barkovich KJ, Moore MK, Hu Q, Shokat KM. Chemical genetic inhibition of DEAD-box proteins using covalent complementarity. Nucleic Acids Res. 2018 09 28; 46(17):8689-8699.
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  19. 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 12; 17(12):2702-2709.
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  20. 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).
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