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/NIGMS, Sponsor Award ID: R01GM081644
  • April 1, 2005 - March 31, 2010 - Highly Selective, Irreversible Protein Kinase Inhibitors, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM071434
  • July 1, 2002 - June 30, 2008 - Membrane Movement Powered by Actin Assembly, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM066229

Education

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. Cuesta A, Wan X, Burlingame AL, Taunton J Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90.  View on PubMed
  2. Cuesta A, Taunton J Lysine-Targeted Inhibitors and Chemoproteomic Probes.  View on PubMed
  3. 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.  View on PubMed
  4. 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.  View on PubMed
  5. Smith GA, Taunton J, Weiss A IL-2Rß abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells.  View on PubMed
  6. 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.  View on PubMed
  7. 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.  View on PubMed
  8. 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.  View on PubMed
  9. Shao S, Murray J, Brown A, Taunton J, Ramakrishnan V, Hegde RS Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes.  View on PubMed
  10. 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.  View on PubMed
  11. 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.  View on PubMed
  12. 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.  View on PubMed
  13. 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.  View on PubMed
  14. 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.  View on PubMed
  15. Smith GA, Uchida K, Weiss A, Taunton J Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling.  View on PubMed
  16. 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.  View on PubMed
  17. 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.  View on PubMed
  18. Okrut J, Prakash S, Wu Q, Kelly MJ, Taunton J Allosteric N-WASP activation by an inter-SH3 domain linker in Nck.  View on PubMed
  19. Bradshaw JM, McFarland JM, Paavilainen VO, Bisconte A, Tam D, Phan VT, Romanov S, Finkle D, Shu J, Patel V, Ton T, Li X, Loughhead DG, Nunn PA, Karr DE, Gerritsen ME, Funk JO, Owens TD, Verner E, Brameld KA, Hill RJ, Goldstein DM, Taunton J Prolonged and tunable residence time using reversible covalent kinase inhibitors.  View on PubMed
  20. Heo KS, Le NT, Cushman HJ, Giancursio CJ, Chang E, Woo CH, Sullivan MA, Taunton J, Yeh ET, Fujiwara K, Abe J Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function.  View on PubMed

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