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. 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
  2. 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
  3. 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
  4. 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 Aug 29; 42(8):112868.  View on PubMed
  5. 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
  6. 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
  7. Guiley KZ, Shokat KM. A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability. Cancer Discov. 2023 01 09; 13(1):56-69.  View on PubMed
  8. Lou K, Wassarman DR, Yang T, Paung Y, Zhang Z, O'Loughlin TA, Moore MK, Egan RK, Greninger P, Benes CH, Seeliger MA, Taunton J, Gilbert LA, Shokat KM. IFITM proteins assist cellular uptake of diverse linked chemotypes. Science. 2022 12 09; 378(6624):1097-1104.  View on PubMed
  9. Peacock DM, Kelly MJS, Shokat KM. Probing the KRas Switch II Groove by Fluorine NMR Spectroscopy. ACS Chem Biol. 2022 Oct 21; 17(10):2710-2715.  View on PubMed
  10. Dai SA, Hu Q, Gao R, Blythe EE, Touhara KK, Peacock H, Zhang Z, von Zastrow M, Suga H, Shokat KM. State-selective modulation of heterotrimeric Gαs signaling with macrocyclic peptides. Cell. 2022 10 13; 185(21):3950-3965.e25.  View on PubMed
  11. Zhang Z, Fan Q, Luo X, Lou K, Weiss WA, Shokat KM. Brain-restricted mTOR inhibition with binary pharmacology. Nature. 2022 09; 609(7928):822-828.  View on PubMed
  12. Smith GA, Padmanabhan A, Lau BH, Pampana A, Li L, Lee CY, Pelonero A, Nishino T, Sadagopan N, Xia VQ, Jain R, Natarajan P, Wu RS, Black BL, Srivastava D, Shokat KM, Chorba JS. Cold shock domain-containing protein E1 is a posttranscriptional regulator of the LDL receptor. Sci Transl Med. 2022 09 14; 14(662):eabj8670.  View on PubMed
  13. Zhang Z, Rohweder PJ, Ongpipattanakul C, Basu K, Bohn MF, Dugan EJ, Steri V, Hann B, Shokat KM, Craik CS. A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. Cancer Cell. 2022 09 12; 40(9):1060-1069.e7.  View on PubMed
  14. Wassarman DR, Bankapalli K, Pallanck LJ, Shokat KM. Tissue-restricted inhibition of mTOR using chemical genetics. Proc Natl Acad Sci U S A. 2022 09 20; 119(38):e2204083119.  View on PubMed
  15. Zhang Z, Morstein J, Ecker AK, Guiley KZ, Shokat KM. Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile. J Am Chem Soc. 2022 09 07; 144(35):15916-15921.  View on PubMed
  16. Zhang Z, Guiley KZ, Shokat KM. Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S). Nat Chem Biol. 2022 11; 18(11):1177-1183.  View on PubMed
  17. Werr L, Plenker D, Dammert MA, Lorenz C, Brägelmann J, Tumbrink HL, Klein S, Schmitt A, Büttner R, Persigehl T, Shokat KM, Wunderlich FT, Schram AM, Peifer M, Sos ML, Reinhardt HC, Thomas RK. CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization. Mol Cancer Ther. 2022 05 04; 21(5):821-830.  View on PubMed
  18. Thorne LG, Bouhaddou M, Reuschl AK, Zuliani-Alvarez L, Polacco B, Pelin A, Batra J, Whelan MVX, Hosmillo M, Fossati A, Ragazzini R, Jungreis I, Ummadi M, Rojc A, Turner J, Bischof ML, Obernier K, Braberg H, Soucheray M, Richards A, Chen KH, Harjai B, Memon D, Hiatt J, Rosales R, McGovern BL, Jahun A, Fabius JM, White K, Goodfellow IG, Takeuchi Y, Bonfanti P, Shokat K, Jura N, Verba K, Noursadeghi M, Beltrao P, Kellis M, Swaney DL, García-Sastre A, Jolly C, Towers GJ, Krogan NJ. Publisher Correction: Evolution of enhanced innate immune evasion by SARS-CoV-2. Nature. 2022 Apr; 604(7905):E14.  View on PubMed
  19. Vasta JD, Peacock DM, Zheng Q, Walker JA, Zhang Z, Zimprich CA, Thomas MR, Beck MT, Binkowski BF, Corona CR, Robers MB, Shokat KM. KRAS is vulnerable to reversible switch-II pocket engagement in cells. Nat Chem Biol. 2022 06; 18(6):596-604.  View on PubMed
  20. Zheng Q, Peacock DM, Shokat KM. Drugging the Next Undruggable KRAS Allele-Gly12Asp. J Med Chem. 2022 02 24; 65(4):3119-3122.  View on PubMed

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