University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Jack Taunton, PhD

Jack Taunton, PhD

Professor, Cellular Molecular Pharmacology, UCSF

Cancer Center Program Memberships

Experimental Therapeutics | Cancer Immunology

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.

Education

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


Professional Experience

  • 1987-1989
    Undergraduate Research, Advisor: Michael P. Doyle, Trinity University Rhodium-catalyzed C-H insertion reactions of diazocarbonyl compounds.
  • 1990-1996
    Graduate Student, Advisor: Stuart Schreiber, Harvard University Discovery and cloning of the first histone deacetylase, HDAC1. Total synthesis of dimethyldynemicin methyl ester, an enediyne antitumor agent.
  • 1996-2000
    Postdoctoral Fellow, Advisor: Tim Mitchison, Harvard Medical School Functional reconstitution of actin assembly by endosomes and lysosomes.
  • 2000-2006
    Assistant Professor, University of California, San Francisco Dept. of Cellular & Molecular Pharmacology
  • 2006-2012
    Associate Professor, University of California, San Francisco Dept. of Cellular & Molecular Pharmacology
  • 2008-2015
    Howard Hughes Medical Institute Investigator
  • 2012-present
    Professor, University of California, San Francisco

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. 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 May 09.
    View on PubMed
  2. 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 Jan 18; 139(2):680-685.
    View on PubMed
  3. 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 Dec 09; 5.
    View on PubMed
  4. 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
  5. 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 Dec 12; 213(13):2885-2896.
    View on PubMed
  6. 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 Oct 20; 64(2):347-361.
    View on PubMed
  7. 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 Aug 04; 63(3):433-44.
    View on PubMed
  8. 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 May 19; 23(5):561-566.
    View on PubMed
  9. 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.
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  10. 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.
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  11. 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
  12. 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
  13. 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.
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  14. 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. Nat Chem Biol. 2015 Jul; 11(7):525-31.
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  15. 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. J Clin Invest. 2015 Mar 02; 125(3):1299-310.
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  16. Ruiz-Saenz A, Sandhu M, Carrasco Y, Maglathlin RL, Taunton J, Moasser MM. Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum. Oncogene. 2015 Oct 08; 34(41):5288-94.
    View on PubMed
  17. London N, Miller RM, Krishnan S, Uchida K, Irwin JJ, Eidam O, Gibold L, Cimermancic P, Bonnet R, Shoichet BK, Taunton J. Covalent docking of large libraries for the discovery of chemical probes. Nat Chem Biol. 2014 Dec; 10(12):1066-72.
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  18. Krishnan S, Miller RM, Tian B, Mullins RD, Jacobson MP, Taunton J. Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis. J Am Chem Soc. 2014 Sep 10; 136(36):12624-30.
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  19. Mackinnon AL, Paavilainen VO, Sharma A, Hegde RS, Taunton J. An allosteric Sec61 inhibitor traps nascent transmembrane helices at the lateral gate. Elife. 2014; 3:e01483.
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  20. Miller RM, Taunton J. Targeting protein kinases with selective and semipromiscuous covalent inhibitors. Methods Enzymol. 2014; 548:93-116.
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