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Benedikt Kessler is Professor of Biochemistry and Mass Spectrometry in the Nuffield Department of Medicine. In this story, Benedikt tells us about his research and how collaborating with industry has been critical to advancing his research discipline and also enabled further collaborations with other industry partners.

Benedikt Kessler alongside quote "Working with industry proved indispensable to advancing the field of ubiquitin biology research and to exploring translational opportunities. Moreover, this alliance also paved the way for further industry collaborations".

What is the focus of your research?

Deubiquitinases (DUBs), a family of ~100 human genes, are proteases that recognise and cleave ubiquitin, a small conserved 76 amino acid protein, from protein substrates. Proteins modified by ubiquitin are affected in their function and fate, thereby modulating most cell biological pathways. Genetic mutations in ubiquitin processing genes including DUBs are linked to cancer, autoimmune, neurodegenerative and neuromuscular disorders.

The Kessler Laboratory has been focusing on ubiquitin biology since the early-2000s when the field was starting to get attention (Nobel Prize in 2004). Still, the biological function of many ubiquitin processing enzymes, including half of the deubiquitylases (DUBs) remain elusive. However, evidence accumulated that DUBs may represent a potentially attractive enzyme family of proteases for drug discovery, in particular in oncology. Small molecules did not exist at that time, and there was some scepticism about targeting DUBs as their catalytic site configuration, reflecting part of the cysteine protease family, seemed too similar in order to develop selective inhibitors.

When did your collaboration with industry begin, and what does the collaboration look like?

In 2010, Cancer Research Technologies (CRT), part of Cancer Research UK (CRUK), launched an initiative to partner with Forma Therapeutics (Boston), Celgene and four leading academic labs in the DUB field in the UK and Europe: my lab from Oxford along with the labs of David Komander from Cambridge, Sylvie Urbe/Mike Clague from Liverpool and Huib Ovaa from Leiden, The Netherlands were involved.

Three years of negotiations were necessary to set up the ‘DUB Alliance’ with the aim of developing small molecule DUB inhibitors as oncology targets. During its operation between 2013 and 2019, when Celgene was acquired by Bristol Myers Squibb (BMS), the ‘DUB Alliance’ produced selective small molecule inhibitors against a panel of DUBs including providing structural insights into selective DUB inhibition for ubiquitin protease 7 (USP7), a DUB considered as a target in Multiple Myeloma.

How has collaborating with industry helped you achieve impact?

These contributions were critical to the research discipline of ubiquitin biology, demonstrating that it is possible to obtain chemical matter for highly selective DUB inhibition with translational potential.

In 2019, BMS resumed the ‘DUB Alliance’, partnering with Liverpool and Oxford, including my lab, and the ARUK funded Oxford Drug Discovery Institute (ODDI), to continue the original work on USP30 as a major target in Parkinson’s disease ‘Neuro DUB Alliance’. These studies are close to generating a USP30 inhibitor clinical candidate (2024).

Also, from these collaborations emerged the possibility of collaborating with Pfizer, who was interested in DUBs as onco targets via their Innovative Technology Enabling Network (ITEN) to increase interactions with key academic partners. Based on this work, a DUB was selected to be pursued as drug candidate with applications in immuno oncology through Pfizer’s Center for Therapeutic Interventions (CTI), a joint venture with Adan Pinto-Fernandez labs since 2019.  

This has provided the framework for the ubiquitin field to drive the development of DUB inhibitors that entered clinical trial stage, such as ubiquitin specific protease 1 (USP1) (Tango Therapeutics, KSQ Therapeutics) to treat solid tumours, and USP30 for the treatment of acute kidney disease, lung fibrosis and Parkinson’s disease (Mission Therapeutics).