James A. Wells

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James A. Wells
Born (1950-04-28) April 28, 1950 (age 73)
NationalityAmerican
EducationUniversity of California, Berkeley (B.A., 1973), Washington State University (Ph.D., 1979)
Known forProtein Engineering
SpouseCarol A Windsor
ChildrenJulian James Windsor-Wells, Natalie Hope Windsor-Wells
AwardsNational Academy of Sciences
Scientific career
FieldsChemical biology, protein engineering
InstitutionsUniversity of California, San Francisco, Genentech, Inc., Sunesis Pharmaceuticals

James Allen Wells (born April 28, 1950) is a Professor of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at the University of California, San Francisco (UCSF)[1] and a member of the National Academy of Sciences. He received his B.A. degrees in biochemistry and psychology from University of California, Berkeley in 1973 and a PhD in biochemistry from Washington State University with Ralph Yount, PhD in 1979. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark in 1982. He is a pioneer in protein engineering, phage display, fragment-based lead discovery, cellular apoptosis, and the cell surface proteome.

Career[edit]

Genentech (1982 - 1998)[edit]

Jim Wells began his independent research career as a co-founding member of the Protein Engineering Department at Genentech. At Genentech, Wells and his group pioneered "gain-of-function engineering" of enzymes (such as subtilisin[2]), growth factors (human growth hormone[3]), and antibodies by site-directed mutagenesis[4] and protein phage display.[5][6] Several biologic products derived directly from these efforts ranging from Pegvisomat (Somavert) an engineered growth hormone antagonist for treatment of acromegaly,  humanization of the Bevacizumab (Avastin) a VEGF antagonist for treating cancers, and engineered proteases developed for popular laundry detergents by Genencor International. His group developed fundamental technologies (cassette mutagenesis, alanine scanning, protein phage display) and protein design principles ("hot-spots" in protein interfaces,[7] additivity of mutational effects, receptor oligomerization in cytokines) commonly used for engineering enzymes, hormones, antibodies, and protein-protein interfaces. With Tony Kosssiakoff and Bart DeVos, they discovered the activation/dimerization mechanism of human growth hormone, a paradigm for cytokine signaling.[8][9]

Sunesis Pharmaceuticals (1998 – 2005)[edit]

In 1998, Wells co-founded Sunesis Pharmaceuticals where he was CSO, and president.  At Sunesis, the group developed a novel technology for site-directed fragment-based drug discovery, Tethering,[10][11] and applied it to cancer and inflammation targets. They were among the first to develop potent small molecules to protein protein interfaces and cryptic allosteric sites considered undruggable.[12] Several of the compounds discovered at Sunesis are now in clinical development. They also discovered the anti-inflammatory drug Lifitegrast, which was subsequently developed by SarCODE[13] and is now sold by Shire for dry eye syndrome.

University of California, San Francisco (2005 – current)[edit]

In 2005, Wells joined the faculty of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at UCSF. He founded the Small Molecule Discovery Center and served as Chair of Pharmaceutical Chemistry for 8 years. His own lab initially focused on the molecular basis of cell death as applied to cancer and inflammation through elaborating native substrates of caspases. His team designed a suite of engineered enzymes for dissecting protease signaling pathways (subtiligase[14] and the SNIPer[15]), E3 ligase substrates (the NEDDylator[16]), a split-Cas9[17] for temporal editing, and allosteric inhibitors, split-kinases[18] and new phosphospecific antibodies[19][20] for probing protein phosphorylation pathways. In 2012, Wells founded the Antibiome Center[21] as part of the Recombinant Antibody Network,[22] devoted to generating human recombinant antibodies at a proteome-wide scale using high throughput platforms for antibody phage display. The Wells Lab now investigates how cell surface proteomes change in health and disease by applying mass spectrometry and protein and antibody engineering, to understand and disrupt human-disease-associated signaling processes.[23][24] Several notable antibody technologies have also been developed including site specific methionine conjugation using redox-activated chemical tagging (ReACT),[25] antibody-based chemically induced dimerizers (AbCID),[26] antibody-Based PROTACs (AbTAC),[27] antibody targeting a proteolytic neoepitope,[28] and cytokine receptor-targeting chimeras (kineTAC).[29]

Awards[edit]

  • 1990 Pfizer Award (given by the American Chemical Society for achievements in enzyme chemistry)
  • 1997 Distinguished Alumni Award, Washington State University, Pullman, WA
  • 1998 Christian B. Anfinsin Award presented by the Protein Society
  • 1998 Vincent du Vignead Award presented by the American Peptide Society
  • 1999 Elected Member to the National Academy of Sciences
  • 2003 Hans Neurath Award presented by the Protein Society
  • 2005 Braisted Award Lecture
  • 2006 Perlman Lecture Award of the ACS Biotechnology Division
  • 2009 Herman S. Bloch Award, University of Chicago, "for scientific excellence in industry"
  • 2010 Merck Award given by the ASBMB
  • 2011 Smissman Award in Medicinal Chemistry given by the American Chemical Society
  • 2011 Inducted into the MedChem Hall of Fame by American Chemical Society
  • 2015 Inducted into the American Academy of Arts & Science
  • 2016 Elected Member of National Academy of Inventors
  • 2017 WSU Regents' Distinguished Alumnus Award, Washington State University, Pullman, WA
  • 2022 UCSF Distinguished Faculty Research Lecture, University of California, San Francisco, CA

References[edit]

  1. ^ "Jim Wells, PhD". UCSF. Retrieved 18 January 2014.
  2. ^ Mitchinson, Colin; Wells, James A. (30 May 1989). "Protein engineering of disulfide bonds in subtilisin BPN'". Biochemistry. 28 (11): 4807–4815. doi:10.1021/bi00437a043. ISSN 0006-2960. PMID 2504281.
  3. ^ Cunningham, B. C.; Wells, J. A. (2 June 1989). "High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis". Science. 244 (4908): 1081–1085. Bibcode:1989Sci...244.1081C. doi:10.1126/science.2471267. ISSN 0036-8075. PMID 2471267.
  4. ^ Wells, James A.; Vasser, Mark; Powers, David B. (1 January 1985). "Cassette mutagenesis: an efficient method for generation of multiple mutations at defined sites". Gene. 34 (2): 315–323. doi:10.1016/0378-1119(85)90140-4. ISSN 0378-1119. PMID 3891521.
  5. ^ Lowman, H. B.; Bass, S. H.; Simpson, N.; Wells, J. A. (12 November 1991). "Selecting high-affinity binding proteins by monovalent phage display". Biochemistry. 30 (45): 10832–10838. doi:10.1021/bi00109a004. ISSN 0006-2960. PMID 1932005.
  6. ^ Matthews, D. J.; Wells, J. A. (21 May 1993). "Substrate phage: selection of protease substrates by monovalent phage display". Science. 260 (5111): 1113–1117. Bibcode:1993Sci...260.1113M. doi:10.1126/science.8493554. ISSN 0036-8075. PMID 8493554.
  7. ^ Clackson, T.; Wells, J. A. (20 January 1995). "A hot spot of binding energy in a hormone-receptor interface". Science. 267 (5196): 383–386. Bibcode:1995Sci...267..383C. doi:10.1126/science.7529940. ISSN 0036-8075. PMID 7529940. S2CID 19380632.
  8. ^ Cunningham, BC; Ultsch, M; De Vos, AM; Mulkerrin, MG; Clauser, KR; Wells, JA (8 November 1991). "Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule". Science. 254 (5033): 821–5. Bibcode:1991Sci...254..821C. doi:10.1126/science.1948064. PMID 1948064.
  9. ^ Clackson, T.; Ultsch, M. H.; Wells, J. A.; de Vos, A. M. (17 April 1998). "Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity". Journal of Molecular Biology. 277 (5): 1111–1128. doi:10.1006/jmbi.1998.1669. ISSN 0022-2836. PMID 9571026.
  10. ^ Erlanson, Daniel A.; Braisted, Andrew C.; Raphael, Darren R.; Randal, Mike; Stroud, Robert M.; Gordon, Eric M.; Wells, James A. (15 August 2000). "Site-directed ligand discovery". Proceedings of the National Academy of Sciences. 97 (17): 9367–9372. Bibcode:2000PNAS...97.9367E. doi:10.1073/pnas.97.17.9367. ISSN 0027-8424. PMC 16870. PMID 10944209.
  11. ^ Erlanson, Daniel A.; Wells, James A.; Braisted, Andrew C. (2004). "Tethering: fragment-based drug discovery". Annual Review of Biophysics and Biomolecular Structure. 33: 199–223. doi:10.1146/annurev.biophys.33.110502.140409. ISSN 1056-8700. PMID 15139811.
  12. ^ Wells, James A.; McClendon, Christopher L. (December 2007). "Reaching for high-hanging fruit in drug discovery at protein–protein interfaces". Nature. 450 (7172): 1001–1009. Bibcode:2007Natur.450.1001W. doi:10.1038/nature06526. ISSN 0028-0836. PMID 18075579. S2CID 205211934.
  13. ^ Semba, Charles P.; Gadek, Thomas R. (2016). "Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease". Clinical Ophthalmology. 10: 1083–1094. doi:10.2147/OPTH.S110557. ISSN 1177-5467. PMC 4910612. PMID 27354762.
  14. ^ Weeks, Amy M.; Wells, James A. (January 2018). "Engineering peptide ligase specificity by proteomic identification of ligation sites". Nature Chemical Biology. 14 (1): 50–57. doi:10.1038/nchembio.2521. ISSN 1552-4469. PMC 5726896. PMID 29155430.
  15. ^ Morgan, Charles W.; Julien, Olivier; Unger, Elizabeth K.; Shah, Nirao M.; Wells, James A. (2014). Turning on caspases with genetics and small molecules. Methods in Enzymology. Vol. 544. pp. 179–213. doi:10.1016/B978-0-12-417158-9.00008-X. ISBN 9780124171589. ISSN 1557-7988. PMC 4249682. PMID 24974291.
  16. ^ Hill, Zachary B.; Pollock, Samuel B.; Zhuang, Min; Wells, James A. (12 October 2016). "Direct Proximity Tagging of Small Molecule Protein Targets Using an Engineered NEDD8 Ligase". Journal of the American Chemical Society. 138 (40): 13123–13126. doi:10.1021/jacs.6b06828. ISSN 1520-5126. PMC 5308480. PMID 27626304.
  17. ^ Nguyen, Duy P.; Miyaoka, Yuichiro; Gilbert, Luke A.; Mayerl, Steven J.; Lee, Brian H.; Weissman, Jonathan S.; Conklin, Bruce R.; Wells, James A. (1 July 2016). "Ligand-binding domains of nuclear receptors facilitate tight control of split CRISPR activity". Nature Communications. 7: 12009. Bibcode:2016NatCo...712009N. doi:10.1038/ncomms12009. ISSN 2041-1723. PMC 4932181. PMID 27363581.
  18. ^ Diaz, Juan E.; Morgan, Charles W.; Minogue, Catherine E.; Hebert, Alexander S.; Coon, Joshua J.; Wells, James A. (19 October 2017). "A Split-Abl Kinase for Direct Activation in Cells". Cell Chemical Biology. 24 (10): 1250–1258.e4. doi:10.1016/j.chembiol.2017.08.007. ISSN 2451-9448. PMC 5650542. PMID 28919041.
  19. ^ Mou, Yun; Zhou, Xin X.; Leung, Kevin; Martinko, Alexander J.; Yu, Jiun-Yann; Chen, Wentao; Wells, James A. (5 December 2018). "Engineering Improved Antiphosphotyrosine Antibodies Based on an Immunoconvergent Binding Motif". Journal of the American Chemical Society. 140 (48): 16615–16624. doi:10.1021/jacs.8b08402. ISSN 1520-5126. PMID 30398859. S2CID 53232022.
  20. ^ Zhou, Xin X.; Bracken, Colton J.; Zhang, Kaihua; Zhou, Jie; Mou, Yun; Wang, Lei; Cheng, Yifan; Leung, Kevin K.; Wells, James A. (14 October 2020). "Targeting Phosphotyrosine in Native Proteins with Conditional, Bispecific Antibody Traps". Journal of the American Chemical Society. 142 (41): 17703–17713. doi:10.1021/jacs.0c08458. ISSN 1520-5126. PMC 8168474. PMID 32924468.
  21. ^ "QBI | The Antibiome Center". qbi.ucsf.edu. Retrieved 15 November 2022.
  22. ^ "Recombinant Antibody Network". recombinant-antibodies.org. Retrieved 15 November 2022.
  23. ^ Martinko, Alexander J.; Truillet, Charles; Julien, Olivier; Diaz, Juan E.; Horlbeck, Max A.; Whiteley, Gordon; Blonder, Josip; Weissman, Jonathan S.; Bandyopadhyay, Sourav; Evans, Michael J.; Wells, James A. (23 January 2018). "Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins". eLife. 7: e31098. doi:10.7554/eLife.31098. ISSN 2050-084X. PMC 5796798. PMID 29359686.
  24. ^ Leung, Kevin K.; Wilson, Gary M.; Kirkemo, Lisa L.; Riley, Nicholas M.; Coon, Joshua J.; Wells, James A. (7 April 2020). "Broad and thematic remodeling of the surfaceome and glycoproteome on isogenic cells transformed with driving proliferative oncogenes". Proceedings of the National Academy of Sciences of the United States of America. 117 (14): 7764–7775. Bibcode:2020PNAS..117.7764L. doi:10.1073/pnas.1917947117. ISSN 1091-6490. PMC 7148585. PMID 32205440.
  25. ^ Elledge, Susanna K.; Tran, Hai L.; Christian, Alec H.; Steri, Veronica; Hann, Byron; Toste, F. Dean; Chang, Christopher J.; Wells, James A. (17 March 2020). "Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation". Proceedings of the National Academy of Sciences of the United States of America. 117 (11): 5733–5740. Bibcode:2020PNAS..117.5733E. doi:10.1073/pnas.1920561117. ISSN 1091-6490. PMC 7084160. PMID 32123103.
  26. ^ Hill, Zachary B.; Martinko, Alexander J.; Nguyen, Duy P.; Wells, James A. (February 2018). "Human antibody-based chemically induced dimerizers for cell therapeutic applications". Nature Chemical Biology. 14 (2): 112–117. doi:10.1038/nchembio.2529. ISSN 1552-4469. PMC 6352901. PMID 29200207.
  27. ^ Cotton, Adam D.; Nguyen, Duy P.; Gramespacher, Josef A.; Seiple, Ian B.; Wells, James A. (20 January 2021). "Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1". Journal of the American Chemical Society. 143 (2): 593–598. doi:10.1021/jacs.0c10008. ISSN 1520-5126. PMC 8154509. PMID 33395526.
  28. ^ Lim, Shion A.; Zhou, Jie; Martinko, Alexander J.; Wang, Yung-Hua; Filippova, Ekaterina V.; Steri, Veronica; Wang, Donghui; Remesh, Soumya G.; Liu, Jia; Hann, Byron; Kossiakoff, Anthony A.; Evans, Michael J.; Leung, Kevin K.; Wells, James A. (15 February 2022). "Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers". Journal of Clinical Investigation. 132 (4): e154604. doi:10.1172/JCI154604. ISSN 1558-8238. PMC 8843743. PMID 35166238.
  29. ^ Pance, Katarina; Gramespacher, Josef A.; Byrnes, James R.; Salangsang, Fernando; Serrano, Juan-Antonio C.; Cotton, Adam D.; Steri, Veronica; Wells, James A. (22 September 2022). "Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins". Nature Biotechnology. 41 (2): 273–281. doi:10.1038/s41587-022-01456-2. ISSN 1087-0156. PMC 9931583. PMID 36138170. S2CID 252465845.
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