James A. Wells

Last updated

James A. Wells
Born (1950-04-28) April 28, 1950 (age 75)
Education University 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
Awards National Academy of Sciences
Scientific career
FieldsChemical biology, protein engineering
Institutions University 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 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.

Contents

Career

Genentech (1982 - 1998)

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)

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)

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

References

  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". Regulated Cell Death Part A: Apoptotic Mechanisms. Methods in Enzymology. Vol. 544. pp. 179–213. doi:10.1016/B978-0-12-417158-9.00008-X. ISBN   978-0-12-417158-9. 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.