University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
James A. Wells, PhD

James A. Wells, PhD

Professor, Department of Pharmaceutical Sciences, UCSF
Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences, UCSF

Cancer Center Program Memberships

Experimental Therapeutics

Research Summary

I have spent 33 years doing research in therapeutic sciences and biotechnology development, first 16 years at Genentech and then 8 years at Sunesis (a company I founded) prior to joining UCSF 9 years ago. At Genentech, my group was among the first to develop gain-of-function engineering of enzymes and proteins by site-directed mutagenesis and phage display. At Sunesis, we developed novel technologies for fragment-based drug discovery, notably the site-directed approach Tethering. My lab at UCSF has developed the N-terminomics technology to characterize the caspase products cleaved during apoptosis. We currently have what we believe is the largest database of proteins that are cleaved by caspases (~2,000 targets in all), as well as targets cleaved in specific cells and their precise cleavage sites identified. More recently, we have extended our proteomics work to serum using the subtiligase tagging technology. This has allowed us to dive to very low abundance proteins in serum. We have also engineered a new small molecule activated protease, called the SNIPer. We have built a catalytic tagging device called the NEDDylator to interrogate molecular binding partners in cellular pathways involving E3 ligases. Recently, we have developed a motif-specific scaffold strategy for producing synthetic monoclonal antibodies specific to post-translational modifications. I am also Director of the Small Molecule Discovery Center (SMDC) at UCSF, a core facility that offers UCSF researchers access to modern small molecule discovery technologies including high-throughput screening, fragment-based drug discovery, and hit-to-lead medicinal chemistry. We have also built the Antibiome Center for generation of renewable recombinant antibodies to the proteome.

Education

University of California, Berkeley, CA, B.A., 1973, Biochemistry
Washington State University, Ph.D., 1979, Biochemistry
Washington State University, Postdoc, 1979-1980, Chemistry
Stanford University Medical School, Postdoc, 1980-1982, Biochemistry


Professional Experience

  • 1982-1986
    Scientist, Genentech, Inc., Dept. of Protein Engineering
  • 1986-1989
    Senior Scientist, Genentech, Inc., Dept. of Protein Engineering
  • 1989-1998
    Staff Scientist, Genentech, Inc., Dept. of Protein Engineering
  • 1988-2005
    Adjunct Asst, Assoc, and Full Professor, University of California, San Francisco, Dept. of Pharmaceutical Chemistry
  • 1998-2005
    President and CSO, Sunesis Pharmaceuticals
  • 2005-present
    Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences, University of California, San Francisco
  • 2005-present
    Director, Small Molecule Discovery Center, University of California, San Francisco

Honors & Awards

  • 1979-1981
    Damon M. Runyon - Walter Winchell Postdoctoral Fellowship
  • 1990
    Pfizer Award (given by the American Chemical Society for achievements in enzyme chemistry)
  • 1998
    Recipient of the Christian B. Anfinsin Award presented by the Protein Society
  • 1998
    Recipient of the Vincent du Vignead Award given by the American Peptide Society
  • 1999
    Elected Member to the National Academy of Sciences
  • 2003
    Recipient of the Hans Neurath Award given by the Protein Society
  • 2006
    Perlman Lecture Award of the ACS biotechnology Division
  • 2017
    Named to first cohort of Chan Zuckerberg Biohub Investigators

Selected Publications

  1. Yueh C, Rettenmaier J, Xia B, Hall DR, Alekseenko A, Porter KA, Barkovich K, Keseru G, Whitty A, Wells JA, Vajda S, Kozakov D. Kinase Atlas: Druggability Analysis of Potential Allosteric Sites in Kinases. J Med Chem. 2019 Jul 05.
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  2. Hertz NT, Adams EL, Weber RA, Shen RJ, O'Rourke MK, Simon DJ, Zebroski H, Olsen O, Morgan CW, Mileur TR, Hitchcock AM, Sinnott Armstrong NA, Wainberg M, Bassik MC, Molina H, Wells JA, Tessier-Lavigne M. Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration. Neuron. 2019 Jun 07.
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  3. Leung KK, Nguyen A, Shi T, Tang L, Ni X, Escoubet L, MacBeth KJ, DiMartino J, Wells JA. Multiomics of azacitidine-treated AML cells reveals variable and convergent targets that remodel the cell-surface proteome. Proc Natl Acad Sci U S A. 2019 01 08; 116(2):695-700.
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  4. Mou Y, Zhou XX, Leung K, Martinko AJ, Yu JY, Chen W, Wells JA. Engineering Improved Antiphosphotyrosine Antibodies Based on an Immunoconvergent Binding Motif. J Am Chem Soc. 2018 Nov 19.
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  5. Henderson AR, Henley MJ, Foster NJ, Peiffer AL, Beyersdorf MS, Stanford KD, Sturlis SM, Linhares BM, Hill ZB, Wells JA, Cierpicki T, Brooks CL, Fierke CA, Mapp AK. Conservation of coactivator engagement mechanism enables small-molecule allosteric modulators. Proc Natl Acad Sci U S A. 2018 09 04; 115(36):8960-8965.
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  6. Hill ME, Kumar A, Wells JA, Hobman TC, Julien O, Hardy JA. The Unique Cofactor Region of Zika Virus NS2B-NS3 Protease Facilitates Cleavage of Key Host Proteins. ACS Chem Biol. 2018 09 21; 13(9):2398-2405.
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  7. Keedy DA, Hill ZB, Biel JT, Kang E, Rettenmaier TJ, Brandão-Neto J, Pearce NM, von Delft F, Wells JA, Fraser JS. An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering. Elife. 2018 06 07; 7.
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  8. Spangler B, Kline T, Hanson J, Li X, Zhou S, Wells JA, Sato AK, Renslo AR. Toward a Ferrous Iron-Cleavable Linker for Antibody-Drug Conjugates. Mol Pharm. 2018 05 07; 15(5):2054-2059.
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  9. Pollock SB, Hu A, Mou Y, Martinko AJ, Julien O, Hornsby M, Ploder L, Adams JJ, Geng H, Müschen M, Sidhu SS, Moffat J, Wells JA. Highly multiplexed and quantitative cell-surface protein profiling using genetically barcoded antibodies. Proc Natl Acad Sci U S A. 2018 03 13; 115(11):2836-2841.
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  10. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, DeBerardinis RJ, Deshmukh M, Di Daniele N, Di Virgilio F, Dixit VM, Dixon SJ, Duckett CS, Dynlacht BD, El-Deiry WS, Elrod JW, Fimia GM, Fulda S, García-Sáez AJ, Garg AD, Garrido C, Gavathiotis E, Golstein P, Gottlieb E, Green DR, Greene LA, Gronemeyer H, Gross A, Hajnoczky G, Hardwick JM, Harris IS, Hengartner MO, Hetz C, Ichijo H, Jäättelä M, Joseph B, Jost PJ, Juin PP, Kaiser WJ, Karin M, Kaufmann T, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Knight RA, Kumar S, Lee SW, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lowe SW, Luedde T, Lugli E, MacFarlane M, Madeo F, Malewicz M, Malorni W, Manic G, Marine JC, Martin SJ, Martinou JC, Medema JP, Mehlen P, Meier P, Melino S, Miao EA, Molkentin JD, Moll UM, Muñoz-Pinedo C, Nagata S, Nuñez G, Oberst A, Oren M, Overholtzer M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pereira DM, Pervaiz S, Peter ME, Piacentini M, Pinton P, Prehn JHM, Puthalakath H, Rabinovich GA, Rehm M, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Ryan KM, Sayan E, Scorrano L, Shao F, Shi Y, Silke J, Simon HU, Sistigu A, Stockwell BR, Strasser A, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Thorburn A, Tsujimoto Y, Turk B, Vanden Berghe T, Vandenabeele P, Vander Heiden MG, Villunger A, Virgin HW, Vousden KH, Vucic D, Wagner EF, Walczak H, Wallach D, Wang Y, Wells JA, Wood W, Yuan J, Zakeri Z, Zhivotovsky B, Zitvogel L, Melino G, Kroemer G. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018 Mar; 25(3):486-541.
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  11. Martinko AJ, Truillet C, Julien O, Diaz JE, Horlbeck MA, Whiteley G, Blonder J, Weissman JS, Bandyopadhyay S, Evans MJ, Wells JA. Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins. Elife. 2018 Jan 23; 7.
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  12. Hill ZB, Martinko AJ, Nguyen DP, Wells JA. Human antibody-based chemically induced dimerizers for cell therapeutic applications. Nat Chem Biol. 2018 02; 14(2):112-117.
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  13. Weeks AM, Wells JA. Engineering peptide ligase specificity by proteomic identification of ligation sites. Nat Chem Biol. 2018 Jan; 14(1):50-57.
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  14. Srinivasan SR, Cesa LC, Li X, Julien O, Zhuang M, Shao H, Chung J, Maillard I, Wells JA, Duckett CS, Gestwicki JE. Heat Shock Protein 70 (Hsp70) Suppresses RIP1-Dependent Apoptotic and Necroptotic Cascades. Mol Cancer Res. 2018 01; 16(1):58-68.
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  15. Diaz JE, Morgan CW, Minogue CE, Hebert AS, Coon JJ, Wells JA. A Split-Abl Kinase for Direct Activation in Cells. Cell Chem Biol. 2017 Oct 19; 24(10):1250-1258.e4.
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  16. Smart AD, Pache RA, Thomsen ND, Kortemme T, Davis GW, Wells JA. Engineering a light-activated caspase-3 for precise ablation of neurons in vivo. Proc Natl Acad Sci U S A. 2017 09 26; 114(39):E8174-E8183.
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  17. Liu TY, Huang HH, Wheeler D, Xu Y, Wells JA, Song YS, Wiita AP. Time-Resolved Proteomics Extends Ribosome Profiling-Based Measurements of Protein Synthesis Dynamics. Cell Syst. 2017 Jun 28; 4(6):636-644.e9.
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  18. Julien O, Wells JA. Caspases and their substrates. Cell Death Differ. 2017 08; 24(8):1380-1389.
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  19. Tran HL, Lexa KW, Julien O, Young TS, Walsh CT, Jacobson MP, Wells JA. Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product. J Am Chem Soc. 2017 02 22; 139(7):2541-2544.
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  20. Lin S, Yang X, Jia S, Weeks AM, Hornsby M, Lee PS, Nichiporuk RV, Iavarone AT, Wells JA, Toste FD, Chang CJ. Redox-based reagents for chemoselective methionine bioconjugation. Science. 2017 02 10; 355(6325):597-602.
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