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.


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
  • 2018
    Breakthrough Science Initiative Award, Ono Pharma Foundation

Selected Publications

  • Oltion K, Carelli JD, Yang T, See SK, Wang HY, Kampmann M, Taunton J. An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes. Cell. 2023. PMID: 36638793
  • 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 May 19. doi: 10.1038/s41589-022-01019-1. PMID: 35590003
  • Wang HY, Yang H, Holm M, Tom H, Oltion K, Al-Khdhairawi AAQ, Weber JF, Blanchard SC, Ruggero D, Taunton J. Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumor eEF1A antagonist SR-A3. Nat Chem 2022 Dec;14(12):1443-1450. PMID: 36123449
  • Juette MF, Carelli JD, Rundlet EJ, Brown A, Shao S, Ferguson A, Wasserman MR, Holm M, Taunton J, Blanchard SC. Didemnin B and ternatin-4 differentially inhibit conformational changes in eEF1A required for aminoacyl-tRNA accommodation into mammalian ribosomes. eLife. 2022 Oct 20;11:e81608. PMID: 36264623
  • 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 Dec 9;378(6624):1097-1104. PMID: 36480603
  • Wan X, Yang T, Cuesta A, Pang X, Balius TE, Irwin JJ, Shoichet BK, Taunton J. Discovery of lysine-targeted eIF4E inhibitors through covalent docking. J Am Chem Soc. 2020 Mar 18;142(11):4960-4964. PMID: 32105459
  • 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 Feb 19;142(7):3392-3400. PMID: 32009391
  • Cuesta A, Taunton J. Lysine-targeted inhibitors and chemoproteomic probes. Annu Rev Biochem. 2019 Jun 20;88:365-381. PMID: 30633551.
  • Smith GA, Taunton J, Weiss A. IL-2Rß abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells. Sci Signal. 2017 Dec 19;10(510). PMID: 29259099.
  • 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. PMID: 28051857
  • Shao S, Murray J, Brown A, Taunton J, Ramakrishnan V, Hegde RS. Decoding mammalian ribosome-mRNA States by translational GTPase complexes. Cell. 2016 Nov 17;167(5):1229-1240. PMID: 27863242
  • 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. PMID: 27018889
  • 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:e10222. PMID: 26651998
  • Okrut J, Prakash S, Wu Q, Kelly MJ, Taunton J (2015). Allosteric N-WASP activation by an inter-SH3 domain linker in Nck. Proc Natl Acad Sci USA. 2015 Nov 24;112(47):E6436-45. PMID: 26554011
  • 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. PMID: 26006010

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