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.

Research Funding

  • March 1, 2020 - February 28, 2025 - Inhibitors of the G protein GNAS which drives pancreatic tumorigenesis, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: R01CA244550
  • February 1, 2018 - January 31, 2023 - Improving the efficacy of mTOR inhibition, Co-Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: R01CA221969
  • April 14, 2016 - March 31, 2020 - Modeling KRAS-Dependent Synthetic Lethality in Human Colon Organoids, Co-Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: U01CA199241
  • September 12, 2014 - August 31, 2019 - Drugging the Switch-II Pocket of K-Ras, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: R01CA190408

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. Gordon DE, Hiatt J, Bouhaddou M, Rezelj VV, Ulferts S, Braberg H, Jureka AS, Obernier K, Guo JZ, Batra J, Kaake RM, Weckstein AR, Owens TW, Gupta M, Pourmal S, Titus EW, Cakir M, Soucheray M, McGregor M, Cakir Z, Jang G, O'Meara MJ, Tummino TA, Zhang Z, Foussard H, Rojc A, Zhou Y, Kuchenov D, Hüttenhain R, Xu J, Eckhardt M, Swaney DL, Fabius JM, Ummadi M, Tutuncuoglu B, Rathore U, Modak M, Haas P, Haas KM, Naing ZZC, Pulido EH, Shi Y, Barrio-Hernandez I, Memon D, Petsalaki E, Dunham A, Marrero MC, Burke D, Koh C, Vallet T, Silvas JA, Azumaya CM, Billesbølle C, Brilot AF, Campbell MG, Diallo A, Dickinson MS, Diwanji D, Herrera N, Hoppe N, Kratochvil HT, Liu Y, Merz GE, Moritz M, Nguyen HC, Nowotny C, Puchades C, Rizo AN, Schulze-Gahmen U, Smith AM, Sun M, Young ID, Zhao J, Asarnow D, Biel J, Bowen A, Braxton JR, Chen J, Chio CM, Chio US, Deshpande I, Doan L, Faust B, Flores S, Jin M, Kim K, Lam VL, Li F, Li J, Li YL, Li Y, Liu X, Lo M, Lopez KE, Melo AA, Moss FR, Nguyen P, Paulino J, Pawar KI, Peters JK, Pospiech TH, Safari M, Sangwan S, Schaefer K, Thomas PV, Thwin AC, Trenker R, Tse E, Tsui TKM, Wang F, Whitis N, Yu Z, Zhang K, Zhang Y, Zhou F, Saltzberg D, Hodder AJ, Shun-Shion AS, Williams DM, White KM, Rosales R, Kehrer T, Miorin L, Moreno E, Patel AH, Rihn S, Khalid MM, Vallejo-Gracia A, Fozouni P, Simoneau CR, Roth TL, Wu D, Karim MA, Ghoussaini M, Dunham I, Berardi F, Weigang S, Chazal M, Park J, Logue J, McGrath M, Weston S, Haupt R, Hastie CJ, Elliott M, Brown F, Burness KA, Reid E, Dorward M, Johnson C, Wilkinson SG, Geyer A, Giesel DM, Baillie C, Raggett S, Leech H, Toth R, Goodman N, Keough KC, Lind AL, Klesh RJ, Hemphill KR, Carlson-Stevermer J, Oki J, Holden K, Maures T, Pollard KS, Sali A, Agard DA, Cheng Y, Fraser JS, Frost A, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Alessi DR, Davies P, Frieman MB, Ideker T, Abate C, Jouvenet N, Kochs G, Shoichet B, Ott M, Palmarini M, Shokat KM, García-Sastre A, Rassen JA, Grosse R, Rosenberg OS, Verba KA, Basler CF, Vignuzzi M, Peden AA, Beltrao P, Krogan NJ Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.  View on PubMed
  2. Zhang Z, Gao R, Hu Q, Peacock H, Peacock DM, Dai S, Shokat KM, Suga H GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf.  View on PubMed
  3. Melnyk JE, Steri V, Nguyen HG, Hann B, Feng FY, Shokat KM The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells.  View on PubMed
  4. 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.  View on PubMed
  5. 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.  View on PubMed
  6. 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.  View on PubMed
  7. 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.  View on PubMed
  8. 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.  View on PubMed
  9. 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.  View on PubMed
  10. 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.  View on PubMed
  11. 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.  View on PubMed
  12. 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.  View on PubMed
  13. Zhang Z, Shokat KM Bifunctional Small-Molecule Ligands of K-Ras Induce Its Association with Immunophilin Proteins.  View on PubMed
  14. Lou K, Gilbert LA, Shokat KM A Bounty of New Challenging Targets in Oncology for Chemical Discovery.  View on PubMed
  15. 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.  View on PubMed
  16. 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.  View on PubMed
  17. 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.  View on PubMed
  18. 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.  View on PubMed
  19. Wong AW, Urisman A, Burlingame AL, Shokat KM Chemically reprogramming the phospho-transfer reaction to crosslink protein kinases to their substrates.  View on PubMed
  20. 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.  View on PubMed

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