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

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. 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 Mar 24.  View on PubMed
  2. 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 Mar 21.  View on PubMed
  3. 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 Feb 28.  View on PubMed
  4. 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
  5. Cagan R, Shokat K. Drugging the undruggable: Ross Cagan interviews Kevan Shokat. Dis Model Mech. 2022 Feb 01; 15(2).  View on PubMed
  6. Melnyk JE, Steri V, Nguyen HG, Hwang YC, Gordan JD, Hann B, Feng FY, Shokat KM. Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1. Oncogene. 2022 Mar; 41(11):1536-1549.  View on PubMed
  7. 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. Evolution of enhanced innate immune evasion by SARS-CoV-2. Nature. 2022 02; 602(7897):487-495.  View on PubMed
  8. Yang G, Francis D, Krycer JR, Larance M, Zhang Z, Novotny CJ, Diaz-Vegas A, Shokat KM, James DE. Dissecting the biology of mTORC1 beyond rapamycin. Sci Signal. 2021 Sep 21; 14(701):eabe0161.  View on PubMed
  9. Ehinger Y, Zhang Z, Phamluong K, Soneja D, Shokat KM, Ron D. Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice. Nat Commun. 2021 07 27; 12(1):4407.  View on PubMed
  10. Tummino TA, Rezelj VV, Fischer B, Fischer A, O'Meara MJ, Monel B, Vallet T, White KM, Zhang Z, Alon A, Schadt H, O'Donnell HR, Lyu J, Rosales R, McGovern BL, Rathnasinghe R, Jangra S, Schotsaert M, Galarneau JR, Krogan NJ, Urban L, Shokat KM, Kruse AC, García-Sastre A, Schwartz O, Moretti F, Vignuzzi M, Pognan F, Shoichet BK. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. Science. 2021 07 30; 373(6554):541-547.  View on PubMed
  11. Thorne LG, Bouhaddou M, Reuschl AK, Zuliani-Alvarez L, Polacco B, Pelin A, Batra J, Whelan MVX, Ummadi M, Rojc A, Turner J, Obernier K, Braberg H, Soucheray M, Richards A, Chen KH, Harjai B, Memon D, Hosmillo M, Hiatt J, Jahun A, Goodfellow IG, Fabius JM, Shokat K, Jura N, Verba K, Noursadeghi M, Beltrao P, Swaney DL, Garcia-Sastre A, Jolly C, Towers GJ, Krogan NJ. Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant. bioRxiv. 2021 Jun 07.  View on PubMed
  12. Tummino TA, Rezelj VV, Fischer B, Fischer A, O'Meara MJ, Monel B, Vallet T, Zhang Z, Alon A, O'Donnell HR, Lyu J, Schadt H, White KM, Krogan NJ, Urban L, Shokat KM, Kruse AC, García-Sastre A, Schwartz O, Moretti F, Vignuzzi M, Pognan F, Shoichet BK. Phospholipidosis is a shared mechanism underlying the in vitro antiviral activity of many repurposed drugs against SARS-CoV-2. bioRxiv. 2021 Mar 24.  View on PubMed
  13. Parker N, Laychur A, Sukwani M, Orwig KE, Oatley JM, Zhang C, Rutaganira FU, Shokat K, Wright WW. Spermatogonial Stem Cell Numbers Are Reduced by Transient Inhibition of GDNF Signaling but Restored by Self-Renewing Replication when Signaling Resumes. Stem Cell Reports. 2021 03 09; 16(3):597-609.  View on PubMed
  14. Reuschl AK, Thorne LG, Zuliani-Alvarez L, Bouhaddou M, Obernier K, Hiatt J, Soucheray M, Turner J, Fabius JM, Nguyen GT, Swaney DL, Rosales R, White KM, Avilés P, Kirby IT, Melnyk JE, Shi Y, Zhang Z, Shokat KM, García-Sastre A, Jolly C, Towers GJ, Krogan NJ. Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant. bioRxiv. 2021 Feb 04.  View on PubMed
  15. Wolpaw AJ, Bayliss R, Büchel G, Dang CV, Eilers M, Gustafson WC, Hansen GH, Jura N, Knapp S, Lemmon MA, Levens D, Maris JM, Marmorstein R, Metallo SJ, Park JR, Penn LZ, Rape M, Roussel MF, Shokat KM, Tansey WP, Verba KA, Vos SM, Weiss WA, Wolf E, Mossé YP. Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers. Cancer Res. 2021 04 01; 81(7):1627-1632.  View on PubMed
  16. White KM, Rosales R, Yildiz S, Kehrer T, Miorin L, Moreno E, Jangra S, Uccellini MB, Rathnasinghe R, Coughlan L, Martinez-Romero C, Batra J, Rojc A, Bouhaddou M, Fabius JM, Obernier K, Dejosez M, Guillén MJ, Losada A, Avilés P, Schotsaert M, Zwaka T, Vignuzzi M, Shokat KM, Krogan NJ, García-Sastre A. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science. 2021 02 26; 371(6532):926-931.  View on PubMed
  17. 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, QCRG Structural Biology Consortium, 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, Zoonomia Consortium, 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. Science. 2020 12 04; 370(6521).  View on PubMed
  18. 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. ACS Cent Sci. 2020 Oct 28; 6(10):1753-1761.  View on PubMed
  19. Melnyk JE, Steri V, Nguyen HG, Hann B, Feng FY, Shokat KM. The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells. Bioorg Med Chem. 2020 10 15; 28(20):115712.  View on PubMed
  20. 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.  View on PubMed

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