Research Summary

My laboratory develops chemical and biochemical tools to illuminate cellular processes relevant to cancer and autoimmune disease. In a major project area, we have designed covalent inhibitors that target protein kinases with extraordinary selectivity. These inhibitors exploit a non-catalytic cysteine in the active site of kinases such as RSK, MSK, NEK2, and BTK. We recently invented a novel and general strategy for targeting cysteines with reversible covalent inhibitors. This strategy has led to the first reversible covalent BTK inhibitors, and a drug candidate derived from these inhibitors is in Phase 2 clinical trials. In a second project, we have discovered a family of cyclic depsipeptides that inhibit the biogenesis of a subset of secreted and membrane proteins involved in cancer and inflammation. Mechanism of action studies revealed that these compounds, termed “cotransins," are direct allosteric modulators of the Sec61 translocon. Cotransins represent a promising series of anti-cancer drugs with an unprecedented mechanism of action.

Research Funding

  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001614
  • September 10, 2007 - July 31, 2012 - Substrate-Selective Inhibitors of Secretory and Membrane Protein Biogenesis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM081644
  • April 1, 2005 - March 31, 2010 - Highly Selective, Irreversible Protein Kinase Inhibitors , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM071434
  • July 1, 2002 - June 30, 2008 - Membrane Movement Powered by Actin Assembly , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM066229


Trinity University, B.S., 06/89, Chemistry
Harvard University, Ph.D., 06/96, Chemistry
Harvard Medical School, Postdoc, 96-2000, Cell Biology

Honors & Awards

  • 1990
    National Science Foundation Predoctoral Fellowship
  • 1993
    Eli Lilly and Co. Predoctoral Fellowship Award
  • 1996
    Life Sciences Research Foundation Postdoctoral Fellowship
  • 2002
    Searle Scholar
  • 2003
    Alfred P. Sloan Fellow
  • 2007
    Brook Byers Award
  • 2008
    Investigator, Howard Hughes Medical Institute
  • 2010
    Excellence in Teaching Award, UCSF School of Medicine

Selected Publications

  1. Yang T, Cuesta A, Wan X, Craven GB, Hirakawa B, Khamphavong P, May JR, Kath JC, Lapek JD, Niessen S, Burlingame AL, Carelli JD, Taunton J. Reversible lysine-targeted probes reveal residence time-based kinase selectivity. Nat Chem Biol. 2022 09; 18(9):934-941.  View on PubMed
  2. Meyer LK, Delgado-Martin C, Sharp PP, Huang BJ, McMinn D, Vincent TL, Ryan T, Horton TM, Wood BL, Teachey DT, Taunton J, Kirk CJ, Hermiston ML. Inhibition of the Sec61 translocon overcomes cytokine-induced glucocorticoid resistance in T-cell acute lymphoblastic leukaemia. Br J Haematol. 2022 07; 198(1):137-141.  View on PubMed
  3. Cuesta A, Wan X, Burlingame AL, Taunton J. Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90. J Am Chem Soc. 2020 02 19; 142(7):3392-3400.  View on PubMed
  4. Cuesta A, Taunton J. Lysine-Targeted Inhibitors and Chemoproteomic Probes. Annu Rev Biochem. 2019 06 20; 88:365-381.  View on PubMed
  5. Shah PS, Link N, Jang GM, Sharp PP, Zhu T, Swaney DL, Johnson JR, Von Dollen J, Ramage HR, Satkamp L, Newton B, Hüttenhain R, Petit MJ, Baum T, Everitt A, Laufman O, Tassetto M, Shales M, Stevenson E, Iglesias GN, Shokat L, Tripathi S, Balasubramaniam V, Webb LG, Aguirre S, Willsey AJ, Garcia-Sastre A, Pollard KS, Cherry S, Gamarnik AV, Marazzi I, Taunton J, Fernandez-Sesma A, Bellen HJ, Andino R, Krogan NJ. Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis. Cell. 2018 12 13; 175(7):1931-1945.e18.  View on PubMed
  6. Lam C, Ferguson ID, Mariano MC, Lin YT, Murnane M, Liu H, Smith GA, Wong SW, Taunton J, Liu JO, Mitsiades CS, Hann BC, Aftab BT, Wiita AP. Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment. Haematologica. 2018 07; 103(7):1218-1228.  View on PubMed
  7. Smith GA, Taunton J, Weiss A. IL-2Rβ abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells. Sci Signal. 2017 Dec 19; 10(510).  View on PubMed
  8. Delgado-Martin C, Meyer LK, Huang BJ, Shimano KA, Zinter MS, Nguyen JV, Smith GA, Taunton J, Winter SS, Roderick JR, Kelliher MA, Horton TM, Wood BL, Teachey DT, Hermiston ML. JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias. Leukemia. 2017 12; 31(12):2568-2576.  View on PubMed
  9. Zhao Q, Ouyang X, Wan X, Gajiwala KS, Kath JC, Jones LH, Burlingame AL, Taunton J. Broad-Spectrum Kinase Profiling in Live Cells with Lysine-Targeted Sulfonyl Fluoride Probes. J Am Chem Soc. 2017 01 18; 139(2):680-685.  View on PubMed
  10. Yang Z, Robinson MJ, Chen X, Smith GA, Taunton J, Liu W, Allen CD. Regulation of B cell fate by chronic activity of the IgE B cell receptor. Elife. 2016 12 09; 5.  View on PubMed
  11. Shao S, Murray J, Brown A, Taunton J, Ramakrishnan V, Hegde RS. Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes. Cell. 2016 11 17; 167(5):1229-1240.e15.  View on PubMed
  12. Baron L, Paatero AO, Morel JD, Impens F, Guenin-Macé L, Saint-Auret S, Blanchard N, Dillmann R, Niang F, Pellegrini S, Taunton J, Paavilainen VO, Demangel C. Mycolactone subverts immunity by selectively blocking the Sec61 translocon. J Exp Med. 2016 12 12; 213(13):2885-2896.  View on PubMed
  13. Josefowicz SZ, Shimada M, Armache A, Li CH, Miller RM, Lin S, Yang A, Dill BD, Molina H, Park HS, Garcia BA, Taunton J, Roeder RG, Allis CD. Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription. Mol Cell. 2016 10 20; 64(2):347-361.  View on PubMed
  14. Rodríguez-Molina JB, Tseng SC, Simonett SP, Taunton J, Ansari AZ. Engineered Covalent Inactivation of TFIIH-Kinase Reveals an Elongation Checkpoint and Results in Widespread mRNA Stabilization. Mol Cell. 2016 08 04; 63(3):433-44.  View on PubMed
  15. Paatero AO, Kellosalo J, Dunyak BM, Almaliti J, Gestwicki JE, Gerwick WH, Taunton J, Paavilainen VO. Apratoxin Kills Cells by Direct Blockade of the Sec61 Protein Translocation Channel. Cell Chem Biol. 2016 05 19; 23(5):561-566.  View on PubMed
  16. Su X, Ditlev JA, Hui E, Xing W, Banjade S, Okrut J, King DS, Taunton J, Rosen MK, Vale RD. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science. 2016 Apr 29; 352(6285):595-9.  View on PubMed
  17. Smith GA, Uchida K, Weiss A, Taunton J. Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling. Nat Chem Biol. 2016 May; 12(5):373-9.  View on PubMed
  18. Heaton NS, Moshkina N, Fenouil R, Gardner TJ, Aguirre S, Shah PS, Zhao N, Manganaro L, Hultquist JF, Noel J, Sachs D, Hamilton J, Leon PE, Chawdury A, Tripathi S, Melegari C, Campisi L, Hai R, Metreveli G, Gamarnik AV, García-Sastre A, Greenbaum B, Simon V, Fernandez-Sesma A, Krogan NJ, Mulder LCF, van Bakel H, Tortorella D, Taunton J, Palese P, Marazzi I. Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection. Immunity. 2016 Jan 19; 44(1):46-58.  View on PubMed
  19. Carelli JD, Sethofer SG, Smith GA, Miller HR, Simard JL, Merrick WC, Jain RK, Ross NT, Taunton J. Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex. Elife. 2015 Dec 10; 4.  View on PubMed
  20. Okrut J, Prakash S, Wu Q, Kelly MJ, Taunton J. Allosteric N-WASP activation by an inter-SH3 domain linker in Nck. Proc Natl Acad Sci U S A. 2015 Nov 24; 112(47):E6436-45.  View on PubMed

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