Professor, Department of Pharmaceutical Sciences, UCSF
Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences, UCSF
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
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1982-1986
Scientist, Genentech, Inc., Dept. of Protein Engineering
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1986-1989
Senior Scientist, Genentech, Inc., Dept. of Protein Engineering
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1989-1998
Staff Scientist, Genentech, Inc., Dept. of Protein Engineering
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1988-2005
Adjunct Asst, Assoc, and Full Professor, University of California, San Francisco, Dept. of Pharmaceutical Chemistry
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1998-2005
President and CSO, Sunesis Pharmaceuticals
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2005-present
Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences, University of California, San Francisco
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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
Selected Publications
- Morgan CW, Diaz JE, Zeitlin SG, Gray DC, Wells JA. Engineered cellular gene-replacement platform for selective and inducible proteolytic profiling. Proc Natl Acad Sci U S A. 2015 Jul 7; 112(27):8344-9.
View on PubMed - Miersch S, Li Z, Hanna R, McLaughlin ME, Hornsby M, Matsuguchi T, Paduch M, Sääf A, Wells J, Koide S, Kossiakoff A, Sidhu SS. Scalable high throughput selection from phage-displayed synthetic antibody libraries. J Vis Exp. 2015; (95):51492.
View on PubMed - Rettenmaier TJ, Sadowsky JD, Thomsen ND, Chen SC, Doak AK, Arkin MR, Wells JA. A small-molecule mimic of a peptide docking motif inhibits the protein kinase PDK1. Proc Natl Acad Sci U S A. 2014 Dec 30; 111(52):18590-5.
View on PubMed - Koerber JT, Hornsby MJ, Wells JA. An improved single-chain Fab platform for efficient display and recombinant expression. J Mol Biol. 2015 Jan 30; 427(2):576-86.
View on PubMed - Roberts TA, Norris FC, Carnaghan H, Savery D, Wells JA, Siow B, Scambler PJ, Pierro A, De Coppi P, Eaton S, Lythgoe MF. In amnio MRI of mouse embryos. PLoS One. 2014; 9(10):e109143.
View on PubMed - Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP, Sviderskiy VO, Olszewski JL, Koerber JT, Xie T, Beausoleil SA, Wells JA, Gygi SP, Schulman BA, Harper JW. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell. 2014 Nov 6; 56(3):360-75.
View on PubMed - Julien O, Kampmann M, Bassik MC, Zorn JA, Venditto VJ, Shimbo K, Agard NJ, Shimada K, Rheingold AL, Stockwell BR, Weissman JS, Wells JA. Unraveling the mechanism of cell death induced by chemical fibrils. Nat Chem Biol. 2014 Nov; 10(11):969-76.
View on PubMed - Arkin MR, Tang Y, Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol. 2014 Sep 18; 21(9):1102-14.
View on PubMed - Wells JA, Kossiakoff AA. Cell biology. New tricks for an old dimer. Science. 2014 May 16; 344(6185):703-4.
View on PubMed - Wiita AP, Hsu GW, Lu CM, Esensten JH, Wells JA. Circulating proteolytic signatures of chemotherapy-induced cell death in humans discovered by N-terminal labeling. Proc Natl Acad Sci U S A. 2014 May 27; 111(21):7594-9.
View on PubMed - Lodge JM, Rettenmaier TJ, Wells JA, Pomerantz WC, Mapp AK. FP Tethering: a screening technique to rapidly identify compounds that disrupt protein-protein interactions. Medchemcomm. 2014 Mar 1; 5:370-375.
View on PubMed - Ashkenazi A, Yuan J, Wells JA. Regulated cell death part A: apoptotic mechanisms. Preface. Methods Enzymol. 2014; 544:xv.
View on PubMed - Morgan CW, Julien O, Unger EK, Shah NM, Wells JA. Turning on caspases with genetics and small molecules. Methods Enzymol. 2014; 544:179-213.
View on PubMed - Wiita AP, Seaman JE, Wells JA. Global analysis of cellular proteolysis by selective enzymatic labeling of protein N-termini. Methods Enzymol. 2014; 544:327-58.
View on PubMed - Ashkenazi A, Wells JA, Yuan J. Methods in Enzymology. Regulated cell death part B--necroptotic, autophagic and other non-apoptotic mechanisms. Preface. Methods Enzymol. 2014; 545:xiii.
View on PubMed - Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013 Nov 28; 503(7477):548-51.
View on PubMed - Wiita AP, Ziv E, Wiita PJ, Urisman A, Julien O, Burlingame AL, Weissman JS, Wells JA. Global cellular response to chemotherapy-induced apoptosis. Elife. 2013; 2:e01236.
View on PubMed - Koerber JT, Thomsen ND, Hannigan BT, Degrado WF, Wells JA. Nature-inspired design of motif-specific antibody scaffolds. Nat Biotechnol. 2013 Oct; 31(10):916-21.
View on PubMed - Carter PJ, Hazuda D, Wells JA. Next generation therapeutics. Curr Opin Chem Biol. 2013 Jun; 17(3):317-9.
View on PubMed - Thomsen ND, Koerber JT, Wells JA. Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation. Proc Natl Acad Sci U S A. 2013 May 21; 110(21):8477-82.
View on PubMed
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