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, Sponsor Award ID: R01CA244550
  • February 1, 2018 - January 31, 2023 - Improving the efficacy of mTOR inhibition , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA221969
  • August 15, 2021 - July 31, 2022 - Tissue-specific pharmacology to enhance healthspan , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R56AG071857
  • April 14, 2016 - March 31, 2021 - Modeling KRAS-Dependent Synthetic Lethality in Human Colon Organoids , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01CA199241
  • September 12, 2014 - August 31, 2020 - Drugging the Switch-II Pocket of K-Ras , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA190408
  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001614
  • May 1, 1996 - March 31, 2013 - A Kinase-Substrate Crosslinker For Mapping Signaling Pathways in Reverse , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01EB001987
  • September 1, 1998 - August 31, 2008 - A Chemical Map of T Cell Signaling , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AI044009
  • May 1, 1996 - May 14, 2003 - ENGINEERING ORTHOGONAL PROTEIN KINASE AND NUCLEOTIDES , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA070331

Education

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

Honors & Awards

  • 2001
    Protein Society Young Investigator Award
  • 2002
    Eli Lilly Award in Biological Chemistry
  • 2020
    Alfred Bader Award in Bioinorganic or Bioorganic Chemistry
  • 2021
    Breakthrough Science Award, Samuel Waxman Cancer Research Foundation
  • 2022
    AACR Award for Outstanding Achievement in Chemistry in Cancer Research
  • 2023
    Vollum Award for Distinguished Accomplishment in Science and Technology, Reed College
  • 2023
    Sjöberg Prize, Swedish Academy of Sciences
  • 2023
    National Academy of Sciences Award for Scientific Discovery

Selected Publications

  1. Fernando MC, Craven GB, Shokat KM. The structure of KRASG12C bound to divarasib highlights features of potent switch-II pocket engagement. Small GTPases. 2024 Dec; 15(1):1-7.  View on PubMed
  2. Wassarman DR, Pfaff P, Paulo JA, Gygi SP, Shokat KM, Kranzusch PJ. Deazaguanylation is a nucleobase-protein conjugation required for type IV CBASS immunity. bioRxiv. 2025 Apr 06.  View on PubMed
  3. Turnham RE, Pitea A, Jang GM, Xu Z, Lim HC, Choi AL, Von Dollen J, Levin RS, Webber JT, McCarthy E, Hu J, Li X, Che L, Singh A, Yoon A, Chan GKL, Kelley RK, Swaney DL, Zhang W, Bandyopadhyay S, Theis FJ, Eckhardt M, Chen X, Shokat KM, Ideker T, Krogan NJ, Gordan JD. HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma. Cancer Res. 2025 Feb 17; 85(4):660-674.  View on PubMed
  4. Ostrem JML, Peters U, Shokat KM. Direct RAS inhibitors turn 10. Nat Chem Biol. 2024 Oct; 20(10):1238-1241.  View on PubMed
  5. Liccardo F, Morstein J, Lin TY, Pampel J, Lang D, Shokat KM, Irannejad R. Subcellular activation of β-adrenergic receptors using a spatially restricted antagonist. Proc Natl Acad Sci U S A. 2024 Oct; 121(40):e2404243121.  View on PubMed
  6. Morstein J, Bowcut V, Fernando M, Yang Y, Zhu L, Jenkins ML, Evans JT, Guiley KZ, Peacock DM, Krahnke S, Lin Z, Taran KA, Huang BJ, Stephen AG, Burke JE, Lightstone FC, Shokat KM. Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket. Cell. 2024 Oct 31; 187(22):6379-6392.e17.  View on PubMed
  7. Ngo U, Shi Y, Woodruff P, Shokat K, DeGrado W, Jo H, Sheppard D, Sundaram AB. IL-13 and IL-17A activate β1 integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to enhance force transmission in airway smooth muscle. Proc Natl Acad Sci U S A. 2024 Aug 20; 121(34):e2401251121.  View on PubMed
  8. Leyte-Vidal A, DeFilippis R, Outhwaite IR, Kwan I, Lee JY, Leavitt C, Miller KB, Rea D, Rangwala AM, Lou K, Patel S, Alvarez A, Shokat KM, Bahar I, Seeliger MA, Shah NP. Absence of ABL1 exon 2-encoded SH3 residues in BCR::ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib. Leukemia. 2024 Sep; 38(9):2046-2050.  View on PubMed
  9. Le Belle JE, Condro M, Cepeda C, Oikonomou KD, Tessema K, Dudley L, Schoenfield J, Kawaguchi R, Geschwind D, Silva AJ, Zhang Z, Shokat K, Harris NG, Kornblum HI. Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity. bioRxiv. 2024 Jul 11.  View on PubMed
  10. Ngo U, Shi Y, Woodruff P, Shokat K, DeGrado W, Jo H, Sheppard D, Sundaram AB. IL-13 and IL-17A Activate β1 Integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to Enhance Force Transmission in Airway Smooth Muscle. bioRxiv. 2024 May 01.  View on PubMed
  11. Zheng Q, Zhang Z, Guiley KZ, Shokat KM. Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D. Nat Chem Biol. 2024 09; 20(9):1114-1122.  View on PubMed
  12. Malakoutikhah M, Mahran R, Gooran N, Masoumi A, Lundell K, Liljeblad A, Guiley K, Dai S, Zheng Q, Zhu L, Shokat KM, Kopra K, Härmä H. Nanomolar Protein Thermal Profiling with Modified Cyanine Dyes. Anal Chem. 2023 12 19; 95(50):18344-18351.  View on PubMed
  13. Liccardo F, Morstein J, Lin TY, Pampel J, Shokat KM, Irannejad R. Selective activation of intracellular β1AR using a spatially restricted antagonist. bioRxiv. 2023 Nov 22.  View on PubMed
  14. Wu T, Hornsby M, Zhu L, Yu JC, Shokat KM, Gestwicki JE. Protocol for performing and optimizing differential scanning fluorimetry experiments. STAR Protoc. 2023 Dec 15; 4(4):102688.  View on PubMed
  15. Haas KM, McGregor MJ, Bouhaddou M, Polacco BJ, Kim EY, Nguyen TT, Newton BW, Urbanowski M, Kim H, Williams MAP, Rezelj VV, Hardy A, Fossati A, Stevenson EJ, Sukerman E, Kim T, Penugonda S, Moreno E, Braberg H, Zhou Y, Metreveli G, Harjai B, Tummino TA, Melnyk JE, Soucheray M, Batra J, Pache L, Martin-Sancho L, Carlson-Stevermer J, Jureka AS, Basler CF, Shokat KM, Shoichet BK, Shriver LP, Johnson JR, Shaw ML, Chanda SK, Roden DM, Carter TC, Kottyan LC, Chisholm RL, Pacheco JA, Smith ME, Schrodi SJ, Albrecht RA, Vignuzzi M, Zuliani-Alvarez L, Swaney DL, Eckhardt M, Wolinsky SM, White KM, Hultquist JF, Kaake RM, García-Sastre A, Krogan NJ. Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets. Nat Commun. 2023 09 27; 14(1):6030.  View on PubMed
  16. Morstein J, Shrestha R, Van QN, López CA, Arora N, Tonelli M, Liang H, Zhou Y, Hancock JF, Stephen AG, Turbyville TJ, Shokat KM. Direct Modulators of K-Ras-Membrane Interactions. ACS Chem Biol. 2023 09 15; 18(9):2082-2093.  View on PubMed
  17. Zhulyn O, Rosenblatt HD, Shokat L, Dai S, Kuzuoglu-Öztürk D, Zhang Z, Ruggero D, Shokat KM, Barna M. Evolutionarily divergent mTOR remodels translatome for tissue regeneration. Nature. 2023 Aug; 620(7972):163-171.  View on PubMed
  18. Shin S, Han MJ, Jedrychowski MP, Zhang Z, Shokat KM, Plas DR, Dephoure N, Yoon SO. mTOR inhibition reprograms cellular proteostasis by regulating eIF3D-mediated selective mRNA translation and promotes cell phenotype switching. Cell Rep. 2023 08 29; 42(8):112868.  View on PubMed
  19. Dugan MP, Ferguson LB, Hertz NT, Chalkley RJ, Burlingame AL, Shokat KM, Parker PJ, Messing RO. Chemical Genetic Identification of PKC Epsilon Substrates in Mouse Brain. Mol Cell Proteomics. 2023 04; 22(4):100522.  View on PubMed
  20. Ruiz-Saenz A, Atreya CE, Wang C, Pan B, Dreyer CA, Brunen D, Prahallad A, Muñoz DP, Ramms DJ, Burghi V, Spassov DS, Fewings E, Hwang YC, Cowdrey C, Moelders C, Schwarzer C, Wolf DM, Hann B, VandenBerg SR, Shokat K, Moasser MM, Bernards R, Gutkind JS, van 't Veer LJ, Coppé JP. A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors. Nat Cancer. 2023 02; 4(2):240-256.  View on PubMed

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