Benedikt Kessler

Benedikt Kessler
Academic background
EducationB.A., Biochemistry
Ph.D., Immunology
Alma materSwiss Federal Institute of Technology
Ludwig Institute for Cancer Research
Academic work
InstitutionsUniversity of Oxford

Benedikt Kessler is a Swiss researcher and academic. He is Professor of Biochemistry and Mass Spectrometry at the Target Discovery Institute, University of Oxford.[1]

Kessler's research has been focused on ubiquitin and protease biology. Some of his work has dealt with defining the molecular signatures in human disease processes and accelerating target discovery in translational research.[2][3] He holds two patents.[4][5]

Kessler is a member of the British Mass Spectrometry Society, the British Society of Cell Biology and the American Association for Cancer Research.[6]

Education[edit]

Kessler received a B.A. in Biochemistry from Swiss Federal Institute of Technology in 1992. He then joined Ludwig Institute for Cancer Research where he received his Ph.D. in Immunology. He completed his post-doctoral training at Harvard Medical School in the laboratory of Hidde Ploegh where he studied the role of proteolysis in antigen processing and presentation.[7][8]

Career[edit]

In 2001, Kessler joined the Harvard Medical School as an Instructor in Pathology. He left Harvard in 2004 and moved to the United Kingdom, where he joined the University of Oxford as a Research Group Leader.[8] Later he started teaching at the University of Oxford, becoming a Full Professor of Biochemistry & Life Science Mass Spectrometry in 2014.[1]

Kessler was part of the DUB Alliance, a group that is working to develop novel drugs against deubiquitylating enzymes (DUBs). He is currently a member of the Innovative Technology Enabling Network (ITEN), a scientific consortium that explores DUBs as cancer targets coordinated by Pfizer.[9]

Research and work[edit]

Kessler has been studying major histocompatibility complex (MHC) class I antigens using HPLC-based analysis since 1993 and mass spectrometry-based approaches to study the ubiquitin-proteasome pathway since 2000. In 2005, he established his own group at the University of Oxford, Nuffield Department of Medicine (NDM), with a focus on ubiquitin and protease biology, biological mass spectrometry and proteomics. Kessler relocated his laboratory to the Target Discovery Institute (TDI) in 2013.

Kessler has made contributions to explain the action of novel clinical drugs (Velcade, Carfilzomib, Kyprolis) for the treatment of Multiple Myeloma patients,[10] and to the discovery of potentially clinically exploitable cancer targets within the ubiquitin system, in particular deubiquitylating enzymes (DUBs).[11][12] The Kessler group also helped to uncover molecular signatures associated with a panel of human diseases via clinical proteomics studies.[13][14]

The Kessler Lab is currently developing chemoproteomics methods to profile active ubiquitin processing enzymes, in particular deubiquitylating enzymes (DUBs) and the dynamic ubiquitome.[15] Ubiquitin-based active site directed probes were developed that allowed the profiling of the active cellular content of the DUB enzyme family.[16] This approach was also used to demonstrate the involvement of otubain 1 (OTUB1) in infection[17] and prostate cancer,[18] the role of USP4[19] and USP47[20] in DNA repair mechanisms and USP18[21] in immuno-oncology. In particular, Kessler's work contributed to the characterisation of small molecule DUB inhibitors as novel potential therapeutic agents against USP30[22][23] in Parkinson's disease, USP28[24] in squamous lung carcinoma and USP7[25] in multiple myeloma.[12][26]

Awards and honors[edit]

  • Cesar Roux Research Award of the Faculty of Medicine, Lausanne University
  • Human Frontier Science Program Organization long-term fellowship
  • Roche Research Foundation post-doctoral fellowship
  • Recipient of a Multiple Myeloma Research Foundation (MMRF) Senior Research Award
  • Member of the British Society of Mass Spectrometry and British Society of Cell Biology
  • Member of the American Association for Cancer Research (AACR)
  • NIH study section member in 2003 and 2004: Bio-warfare and infectious diseases
  • Wellcome Trust VIP Award 2005
  • MRC New Investigator Award 2006-2009

Selected publications[edit]

  • Hemelaar, J., Galardy, P. J., Borodovsky, A., Kessler, B. M., Ploegh, H. L., & Ovaa, H. (2004). Chemistry-based functional proteomics: mechanism-based activity-profiling tools for ubiquitin and ubiquitin-like specific proteases.. Journal of proteome research, 3(2), 268-276.
  • Altun, M., Galardy, P. J., Shringarpure, R., Hideshima, T., LeBlanc, R., Anderson, K. C., . . . Kessler, B. M. (2005). Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells.. Cancer research, 65(17), 7896-7901.
  • Edelmann, M. J., Kramer, H. B., Altun, M., & Kessler, B. M. (2010). Post-translational modification of the deubiquitinating enzyme otubain 1 modulates active RhoA levels and susceptibility to Yersinia invasion.. The FEBS journal, 277(11), 2515-2530.
  • Kramer, H. B., Simmons, A., Gasper-Smith, N., Borrow, P., Lavender, K. J., Qin, L., . . . Haynes, B. F. (2010). Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.. PLoS Pathog, 6(5).
  • Parsons, J. L., Dianova, I. I., Khoronenkova, S. V., Edelmann, M. J., Kessler, B. M., & Dianov, G. L. (2011). USP47 is a deubiquitylating enzyme that regulates base excision repair by controlling steady-state levels of DNA polymerase β.. Molecular cell, 41(5), 609-615.
  • Altun, M., Kramer, H. B., Willems, L. I., McDermott, J. L., Leach, C. A., Goldenberg, S. J., . . . Kogan, E. (2011). Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes.. Chemistry & biology, 18(11), 1401-1412.
  • Chauhan, D., Tian, Z., Nicholson, B., Kumar, K. G. S., Zhou, B., Carrasco, R., . . . Kodrasov, M. P. (2012). A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance.. Cancer cell, 22(3), 345-358.
  • Konietnzy, R., Wijnhoven, P., Blackford, A. N., Kessler, B., Travers, J., Nishi, R., & Jackson, S. P. (2015). USP4 auto-deubiquitylation promotes homologous recombination. Molecular Cell, 60(3), 362-373.
  • Iglesias-Gato, D., Chuan, Y. -C., Jiang, N., Svensson, C., Bao, J., Shang, Z., . . . Flores-Morales, A. (2015). Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo.. Molecular cancer, 14, 88.
  • Huang, H., van Dullemen, L., Akhtar, M., Lo Faro, M. L., Yu, Z., Valli, A., . . . Kessler, B. (2018). Proteo-metabolomics reveals compensation between ischemic and non-injured contralateral kidneys after reperfusion. Scientific Reports, 8.
  • Salah, E., Zhang, P., Charles, P., Mathea, S., Damianou, A., Fischer, R., . . . Scott, H. (2019). Comprehensive Landscape of Active Deubiquitinating Enzymes Profiled by Advanced Chemoproteomics. Frontiers in Chemistry, 7.

References[edit]

  1. ^ a b "Benedikt Kessler".
  2. ^ "Benedikt Kessler - Google Scholar".
  3. ^ Wang, E. W.; Kessler, B. M.; Borodovsky, A.; Cravatt, B. F.; Bogyo, M.; Ploegh, H. L.; Glas, R. (2000). "Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity". Proceedings of the National Academy of Sciences of the United States of America. 97 (18): 9990–9995. Bibcode:2000PNAS...97.9990W. doi:10.1073/pnas.180328897. PMC 27648. PMID 10954757.
  4. ^ "Semisynthetic protein-based site-directed probes for identification and inhibition of active sites, and methods therefore".
  5. ^ "Active Site Probes".
  6. ^ "Benedikt M Kessler".
  7. ^ Kessler, Benedikt M.; Glas, Rickard; Ploegh, Hidde L. (2002). "MHC class I antigen processing regulated by cytosolic proteolysis—short cuts that alter peptide generation". Molecular Immunology. 39 (3–4): 171–179. doi:10.1016/S0161-5890(02)00100-1. PMID 12200049.
  8. ^ a b "Professor Benedikt Kessler".
  9. ^ "Pfizer Establishes New Partnering Model For Early-Stage Academic Research".
  10. ^ Altun, Mikael; Galardy, Paul J.; Shringarpure, Reshma; Hideshima, Teru; Leblanc, Richard; Anderson, Kenneth C.; Ploegh, Hidde L.; Kessler, Benedikt M. (2005). "Effects of PS-341 on the Activity and Composition of Proteasomes in Multiple Myeloma Cells". Cancer Research. 65 (17): 7896–7901. doi:10.1158/0008-5472.CAN-05-0506. PMID 16140960.
  11. ^ Altun, M.; Walter, T. S.; Kramer, H. B.; Herr, P.; Iphöfer, A.; Boström, J.; David, Y.; Komsany, A.; Ternette, N.; Navon, A.; Stuart, D. I.; Ren, J.; Kessler, B. M. (2015). "The Human Otubain2-Ubiquitin Structure Provides Insights into the Cleavage Specificity of Poly-Ubiquitin-Linkages". PLOS ONE. 10 (1): e0115344. Bibcode:2015PLoSO..1015344A. doi:10.1371/journal.pone.0115344. PMC 4295869. PMID 25590432.
  12. ^ a b Chauhan, Dharminder; Tian, Ze; Nicholson, Benjamin; Kumar, K.G. Suresh; Zhou, Bin; Carrasco, Ruben; McDermott, Jeffrey L.; Leach, Craig A.; Fulcinniti, Mariaterresa; Kodrasov, Matthew P.; Weinstock, Joseph; Kingsbury, William D.; Hideshima, Teru; Shah, Parantu K.; Minvielle, Stephane; Altun, Mikael; Kessler, Benedikt M.; Orlowski, Robert; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C. (2012). "A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance". Cancer Cell. 22 (3): 345–358. doi:10.1016/j.ccr.2012.08.007. PMC 3478134. PMID 22975377.
  13. ^ Kramer, Holger B.; Lavender, Kerry J.; Qin, Li; Stacey, Andrea R.; Liu, Michael K. P.; Di Gleria, Katalin; Simmons, Alison; Gasper-Smith, Nancy; Haynes, Barton F.; McMichael, Andrew J.; Borrow, Persephone; Kessler, Benedikt M. (2010). "Elevation of Intact and Proteolytic Fragments of Acute Phase Proteins Constitutes the Earliest Systemic Antiviral Response in HIV-1 Infection". PLOS Pathogens. 6 (5): e1000893. doi:10.1371/journal.ppat.1000893. PMC 2865525. PMID 20463814.
  14. ^ Huang, Honglei; Van Dullemen, Leon F. A.; Akhtar, Mohammed Z.; Faro, Maria-Letizia Lo; Yu, Zhanru; Valli, Alessandro; Dona, Anthony; Thézénas, Marie-Laëtitia; Charles, Philip D.; Fischer, Roman; Kaisar, Maria; Leuvenink, Henri G. D.; Ploeg, Rutger J.; Kessler, Benedikt M. (2018). "Proteo-metabolomics reveals compensation between ischemic and non-injured contralateral kidneys after reperfusion". Scientific Reports. 8 (1): 8539. Bibcode:2018NatSR...8.8539H. doi:10.1038/s41598-018-26804-8. PMC 5986744. PMID 29867102.
  15. ^ Pinto-Fernández, Adán; Davis, Simon; Schofield, Abigail B.; Scott, Hannah C.; Zhang, Ping; Salah, Eidarus; Mathea, Sebastian; Charles, Philip D.; Damianou, Andreas; Bond, Gareth; Fischer, Roman; Kessler, Benedikt M. (2019). "Comprehensive Landscape of Active Deubiquitinating Enzymes Profiled by Advanced Chemoproteomics". Frontiers in Chemistry. 7: 592. Bibcode:2019FrCh....7..592P. doi:10.3389/fchem.2019.00592. PMC 6727631. PMID 31555637.
  16. ^ Borodovsky, Anna; Ovaa, Huib; Kolli, Nagamalleswari; Gan-Erdene, Tudeviin; Wilkinson, Keith D.; Ploegh, Hidde L.; Kessler, Benedikt M. (2002). "Chemistry-Based Functional Proteomics Reveals Novel Members of the Deubiquitinating Enzyme Family". Chemistry & Biology. 9 (10): 1149–1159. doi:10.1016/S1074-5521(02)00248-X. PMID 12401499.
  17. ^ Edelmann, M. J.; Kramer, H. B.; Altun, M.; Kessler, B. M. (2010). "Post-translational modification of the deubiquitinating enzyme otubain 1 modulates active RhoA levels and susceptibility to Yersinia invasion". The FEBS Journal. 277 (11): 2515–30. doi:10.1111/j.1742-4658.2010.07665.x. PMID 20553488.
  18. ^ Iglesias-Gato, Diego; Chuan, Yin-Choy; Jiang, Ning; Svensson, Charlotte; Bao, Jing; Paul, Indranil; Egevad, Lars; Kessler, Benedikt M.; Wikström, Pernilla; Niu, Yuanjie; Flores-Morales, Amilcar (2015). "OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo". Molecular Cancer. 14 (1): 8. doi:10.1186/s12943-014-0280-2. PMC 4320819. PMID 25623341.
  19. ^ Wijnhoven, Paul; Konietzny, Rebecca; Blackford, Andrew N.; Travers, Jonathan; Kessler, Benedikt M.; Nishi, Ryotaro; Jackson, Stephen P. (2015). "USP4 Auto-Deubiquitylation Promotes Homologous Recombination". Molecular Cell. 60 (3): 362–373. doi:10.1016/j.molcel.2015.09.019. PMC 4643306. PMID 26455393.
  20. ^ Parsons, Jason L.; Dianova, Irina I.; Khoronenkova, Svetlana V.; Edelmann, Mariola J.; Kessler, Benedikt M.; Dianov, Grigory L. (2011). "USP47 Is a Deubiquitylating Enzyme that Regulates Base Excision Repair by Controlling Steady-State Levels of DNA Polymerase β". Molecular Cell. 41 (5): 609–615. doi:10.1016/j.molcel.2011.02.016. PMID 21362556.
  21. ^ Pinto-Fernandez, Adan (20 November 2020). "Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity". British Journal of Cancer. 124 (4): 817–830. doi:10.1038/s41416-020-01167-y. PMC 7884788. PMID 33214684.
  22. ^ Rusilowicz-Jones, Emma (7 July 2020). "USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation". Life Sci Alliance. 3 (8): e202000768. doi:10.26508/lsa.202000768. PMC 7362391. PMID 32636217.
  23. ^ O'Brien, Darragh (28 June 2023). "Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides". Mol Cell Proteomics. 22 (8): 100609. doi:10.1016/j.mcpro.2023.100609. PMC 10400906. PMID 37385347.
  24. ^ Ruiz, Josue (12 October 2021). "USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma". eLife. 10. doi:10.7554/eLife.71596. PMC 8553340. PMID 34636321.
  25. ^ Altun, Mikael; Kramer, Holger B.; Willems, Lianne I.; McDermott, Jeffrey L.; Leach, Craig A.; Goldenberg, Seth J.; Kumar, K.G. Suresh; Konietzny, Rebecca; Fischer, Roman; Kogan, Edward; MacKeen, Mukram M.; McGouran, Joanna; Khoronenkova, Svetlana V.; Parsons, Jason L.; Dianov, Grigory L.; Nicholson, Benjamin; Kessler, Benedikt M. (2011). "Activity-Based Chemical Proteomics Accelerates Inhibitor Development for Deubiquitylating Enzymes". Chemistry & Biology. 18 (11): 1401–1412. doi:10.1016/j.chembiol.2011.08.018. PMID 22118674.
  26. ^ Turnbull, Andrew P.; Ioannidis, Stephanos; Krajewski, Wojciech W.; Pinto-Fernandez, Adan; Heride, Claire; Martin, Agnes C. L.; Tonkin, Louise M.; Townsend, Elizabeth C.; Buker, Shane M.; Lancia, David R.; Caravella, Justin A.; Toms, Angela V.; Charlton, Thomas M.; Lahdenranta, Johanna; Wilker, Erik; Follows, Bruce C.; Evans, Nicola J.; Stead, Lucy; Alli, Cristina; Zarayskiy, Vladislav V.; Talbot, Adam C.; Buckmelter, Alexandre J.; Wang, Minghua; McKinnon, Crystal L.; Saab, Fabienne; McGouran, Joanna F.; Century, Hannah; Gersch, Malte; Pittman, Marc S.; et al. (2017). "Molecular basis of USP7 inhibition by selective small-molecule inhibitors" (PDF). Nature. 550 (7677): 481–486. Bibcode:2017Natur.550..481T. doi:10.1038/nature24451. PMC 6029662. PMID 29045389.

External links[edit]

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