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

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. Glasgow A, Glasgow J, Limonta D, Solomon P, Lui I, Zhang Y, Nix MA, Rettko NJ, Zha S, Yamin R, Kao K, Rosenberg OS, Ravetch JV, Wiita AP, Leung KK, Lim SA, Zhou XX, Hobman TC, Kortemme T, Wells JA. Engineered ACE2 receptor traps potently neutralize SARS-CoV-2. Proc Natl Acad Sci U S A. 2020 Oct 22.
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  2. Bracken CJ, Lim SA, Solomon P, Rettko NJ, Nguyen DP, Zha BS, Schaefer K, Byrnes JR, Zhou J, Lui I, Liu J, Pance K, Zhou XX, Leung KK, Wells JA. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2. Nat Chem Biol. 2020 Oct 20.
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  3. Zhou XX, Bracken CJ, Zhang K, Zhou J, Mou Y, Wang L, Cheng Y, Leung KK, Wells JA. Targeting Phosphotyrosine in Native Proteins with Conditional, Bispecific Antibody Traps. J Am Chem Soc. 2020 Sep 29.
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  4. Zhou J, Li S, Leung KK, O'Donovan B, Zou JY, DeRisi JL, Wells JA. Deep profiling of protease substrate specificity enabled by dual random and scanned human proteome substrate phage libraries. Proc Natl Acad Sci U S A. 2020 Sep 24.
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  5. Zamecnik CR, Rajan JV, Yamauchi KA, Mann SA, Loudermilk RP, Sowa GM, Zorn KC, Alvarenga BD, Gaebler C, Caskey M, Stone M, Norris PJ, Gu W, Chiu CY, Ng D, Byrnes JR, Zhou XX, Wells JA, Robbiani DF, Nussenzweig MC, DeRisi JL, Wilson MR. ReScan, a Multiplex Diagnostic Pipeline, Pans Human Sera for SARS-CoV-2 Antigens. Cell Rep Med. 2020 Sep 24; 100123.
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  6. Byrnes JR, Zhou XX, Lui I, Elledge SK, Glasgow JE, Lim SA, Loudermilk RP, Chiu CY, Wang TT, Wilson MR, Leung KK, Wells JA. Competitive SARS-CoV-2 Serology Reveals Most Antibodies Targeting the Spike Receptor-Binding Domain Compete for ACE2 Binding. mSphere. 2020 09 16; 5(5).
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  7. Elledge SK, Zhou XX, Byrnes JR, Martinko AJ, Lui I, Pance K, Lim SA, Glasgow JE, Glasgow AA, Turcios K, Iyer N, Torres L, Peluso MJ, Henrich TJ, Wang TT, Tato CM, Leung KK, Greenhouse B, Wells JA. Engineering luminescent biosensors for point-of-care SARS-CoV-2 antibody detection. medRxiv. 2020 Aug 21.
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  8. Bracken CJ, Lim SA, Solomon P, Rettko NJ, Nguyen DP, Zha BS, Schaefer K, Byrnes JR, Zhou J, Lui I, Liu J, Pance K, Zhou XX, Leung KK, Wells JA. Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike. bioRxiv. 2020 Aug 10.
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  9. Glasgow A, Glasgow J, Limonta D, Solomon P, Lui I, Zhang Y, Nix MA, Rettko NJ, Lim SA, Zha S, Yamin R, Kao K, Rosenberg OS, Ravetch JV, Wiita AP, Leung KK, Zhou XX, Hobman TC, Kortemme T, Wells JA. Engineered ACE2 receptor traps potently neutralize SARS-CoV-2. bioRxiv. 2020 Aug 01.
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  10. Lim DC, Joukov V, Rettenmaier TJ, Kumagai A, Dunphy WG, Wells JA, Yaffe MB. Redox priming promotes Aurora A activation during mitosis. Sci Signal. 2020 Jul 21; 13(641).
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  11. Lim SA, Wells JA. Split enzymes: Design principles and strategy. Methods Enzymol. 2020; 644:275-296.
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  12. Byrnes JR, Zhou XX, Lui I, Elledge SK, Glasgow JE, Lim SA, Loudermilk R, Chiu CY, Wilson MR, Leung KK, Wells JA. A SARS-CoV-2 serological assay to determine the presence of blocking antibodies that compete for human ACE2 binding. medRxiv. 2020 May 29.
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  13. Harvey EP, Hauseman ZJ, Cohen DT, Rettenmaier TJ, Lee S, Huhn AJ, Wales TE, Seo HS, Luccarelli J, Newman CE, Guerra RM, Bird GH, Dhe-Paganon S, Engen JR, Wells JA, Walensky LD. Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering. Cell Chem Biol. 2020 Jun 18; 27(6):647-656.e6.
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  14. Moroz A, Wang YH, Sharib JM, Wei J, Zhao N, Huang Y, Chen Z, Martinko AJ, Zhuo J, Lim SA, Zhang LH, Seo Y, Carlin S, Leung KK, Collisson EA, Kirkwood KS, Wells JA, Evans MJ. Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer. Clin Cancer Res. 2020 Jul 15; 26(14):3608-3615.
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  15. Kagan J, Moritz RL, Mazurchuk R, Lee JH, Kharchenko PV, Rozenblatt-Rosen O, Ruppin E, Edfors F, Ginty F, Goltsev Y, Wells JA, LaCava J, Riesterer JL, Germain RN, Shi T, Chee MS, Budnik BA, Yates JR, Chait BT, Moffitt JR, Smith RD, Srivastava S. National Cancer Institute Think-Tank Meeting Report on Proteomic Cartography and Biomarkers at the Single-Cell Level: Interrogation of Premalignant Lesions. J Proteome Res. 2020 05 01; 19(5):1900-1912.
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  16. Leung KK, Wilson GM, Kirkemo LL, Riley NM, Coon JJ, Wells JA. Broad and thematic remodeling of the surfaceome and glycoproteome on isogenic cells transformed with driving proliferative oncogenes. Proc Natl Acad Sci U S A. 2020 04 07; 117(14):7764-7775.
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  17. Elledge SK, Tran HL, Christian AH, Steri V, Hann B, Toste FD, Chang CJ, Wells JA. Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation. Proc Natl Acad Sci U S A. 2020 03 17; 117(11):5733-5740.
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  18. Weeks AM, Wells JA. N-Terminal Modification of Proteins with Subtiligase Specificity Variants. Curr Protoc Chem Biol. 2020 03; 12(1):e79.
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  19. Wei J, Leung K, Truillet C, Ruggero D, Wells JA, Evans MJ. Profiling the Surfaceome Identifies Therapeutic Targets for Cells with Hyperactive mTORC1 Signaling. Mol Cell Proteomics. 2020 02; 19(2):294-307.
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  20. Weeks AM, Wells JA. Subtiligase-Catalyzed Peptide Ligation. Chem Rev. 2020 03 25; 120(6):3127-3160.
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