Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome

Lead Research Organisation: University of Oxford
Department Name: Target Discovery Institute


Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.


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Clancy A (2021) The deubiquitylase USP9X controls ribosomal stalling. in The Journal of cell biology

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Kessler BM (2021) DUB esterase activity further decodes ubiquitin's enigma. in Proceedings of the National Academy of Sciences of the United States of America

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Mulder MPC (2020) Editorial: Probing the Ubiquitin Landscape. in Frontiers in chemistry

Description DUB metalloproteases are important anti-cancer targets, potentially also for the treatment of muscle dystrophies (ongoing research)
Research has contributed to understand the role of DUBs (including DUB metalloproteases), but also protein acetylation in muscle ageing.
Publication: Deacetylation Inhibition Reverses PABPN1-Dependent Muscle Wasting. iScience 2019, 10.1016/j.isci.2019.01.024

Defining the cellular landscape of endogenous active deubiquitinases (DUBs), including DUB metalloprotease:
Publication: Comprehensive Landscape of Active Deubiquitinating Enzymes Profiled by Advanced Chemoproteomics. Front Chem. 2019 Aug 29;7:592. doi: 10.3389/fchem.2019.00592

Role of the ubiquitin system (including DUBs) in myogenic differentiation:
Publication: Cytoskeletal disorganization underlies PABPN1-mediated myogenic disability. Sci Rep. 2020 Oct 19;10(1):17621. doi: 10.1038/s41598-020-74676-8
Exploitation Route Contributed to extension of funding for CRT/Forma DUB Alliance; helped to justify Pfizer ITEN and CTI Awards
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

Description Suggestion of sirtinol as an anti-ageing / anti-muscular dystrophy drug Publication - Deacetylation Inhibition Reverses PABPN1-Dependent Muscle Wasting. iScience 2019, 10.1016/j.isci.2019.01.024 Publication - Cytoskeletal disorganization underlies PABPN1-mediated myogenic disability. Sci Rep. 2020 Oct 19;10(1):17621. doi: 10.1038/s41598-020-74676-8 Publication - Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity. Br J Cancer. 2021 Feb;124(4):817-830. doi: 10.1038/s41416-020-01167-y.
First Year Of Impact 2019
Sector Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

Description Innovative Target Exploration Network (ITEN) - Pfizer
Amount £550,000 (GBP)
Organisation Pfizer Global R & D 
Sector Private
Country United States
Start 04/2018 
End 03/2021
Description Modulation of the interferon stimulated gene (ISG) responses by TCM products and plant miRNAs
Amount £258,781 (GBP)
Funding ID 2018-I2M-2-002 
Organisation Academy of Medicine 
Sector Academic/University
Country Singapore
Start 01/2020 
End 12/2022
Title Acetylome methodology for mass spectrometry 
Description Mass spectrometry based determination of protein acetylation on a proteomic level - methodology 
Type Of Material Biological samples 
Year Produced 2019 
Provided To Others? Yes  
Impact Reduced poly(A)-binding protein nuclear 1 (PABPN1) levels cause aging-associated muscle wasting. PABPN1 is a multifunctional regulator of mRNA processing. To elucidate the molecular mechanisms causing PABPN1-mediated muscle wasting, we compared the transcriptome with the proteome in mouse muscles expressing short hairpin RNA to PABPN1 (shPab). We found greater variations in the proteome than in mRNA expression profiles. Protein accumulation in the shPab proteome was concomitant with reduced proteasomal activity. Notably, protein acetylation appeared to be decreased in shPab versus control proteomes (63%). Acetylome profiling in shPab muscles revealed prominent peptide deacetylation associated with elevated sirtuin-1 (SIRT1) deacetylase. We show that SIRT1 mRNA levels are controlled by PABPN1 via alternative polyadenylation site utilization. Most importantly, SIRT1 deacetylase inhibition by sirtinol increased PABPN1 levels and reversed muscle wasting. We suggest that perturbation of a multifactorial regulatory loop involving PABPN1 and SIRT1 plays an imperative role in aging-associated muscle wasting. iScience. 2019 Feb 22;12:318-332 
Description Bicycle Therapeutics Collaboration 
Organisation Bicycle Therapeutics
Country United Kingdom 
Sector Private 
PI Contribution Bicycle Therapeutics has developed cyclic peptide-based molecules conjugated to known cytoxtoxins (Bicycle Toxin Conjugates - BTCs) for selective delivery to tumours. This concept has proven to be successful with improved tumour tissue penetration as compared to established antibody drug conjugate (ADC) delivery. However, details of precise localisation and quantities of both intact conjugate and toxin reaching target tumours are lacking. Such information is crucial to enhance the understanding the disposition properties of the BTC in the tumour, differentiate between the BTC and ADC platform and enable the future discovery of the next generation of advanced BTC's. The present work plan aims make use of the Kessler Lab (CMD/TDI) advanced mass spectrometry platforms to address these issues.
Collaborator Contribution Bicycle Therapeutics is providing the funding for this project and will also provide reagents and biological samples for advanced MS analysis.
Impact This project has just started.
Start Year 2022
Description Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science 
Organisation Peking Union Medical College
Country China 
Sector Academic/University 
PI Contribution Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2018-I2M-2-002) Member of the Chinese Oxford Institute (COI)
Collaborator Contribution This is a research collaboration across the CAMS network to explore the molecular mechanisms underlying Traditional Chinese Medicine (TCM) with anti-inflammatory properties for the treatment of human diseases with associated chronic / auto-immune inflammation.
Impact Ongoing
Start Year 2019
Description ITEN Pfizer 
Organisation Pfizer Global R & D
Country United States 
Sector Private 
PI Contribution Pfizer Establishes New Partnering Model for Early-Stage Academic Research
Collaborator Contribution The University of Cambridge and the University of Oxford are the first to participate in the ITEN model in the United Kingdom, and the University of Texas Southwestern (UTSW) is the first to participate in the United States. Pfizer is seeking to selectively include other institutions to be part of the ITEN model.
Impact Collaborative project on deubiquitylating enzymes early target discovery
Start Year 2017
Description KRONOS - KBTDB4 Recruiting of Neo-Substrates - Sponsored Research Award with Oxford Science Enterprises 
Organisation Science Oxford
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Sponsored Research Agreement (SRA) to capitalise on insight that the small molecule UM171 and derivatives likely act as a 'molecular glue', through the E3 ligase KBTBD4 targeting the Co-REST complex, LSD1 and potential novel substrates for degradation. Pilot study for the unbiased identification of novel degraders from chemical libraries.
Collaborator Contribution Oxford Science Enterprises (OSE) is providing the funding in form of a Sponsored Research Agreement (SRA) for this project.
Impact N/A - just started in Jan 2023
Start Year 2023
Description Pfizer CTI - Oxford Partnership 
Organisation Pfizer Global R & D
Country United States 
Sector Private 
PI Contribution Pfizer Centre for Therapeutic Intervention (CTI) has formed a partnership with the University of Oxford based on a co-discovery model to develop novel drugs against an immuno-oncology target that was studied in the Kessler group.
Collaborator Contribution Grant funding for the Kessler lab
Impact 10.1038/s41416-020-01167-y
Start Year 2021
Title Deacetylation Inhibition Reverses PABPN1-Dependent Muscle Wasting 
Description Sirtinol is a deacetylase inhibitor, mainly inhibiting Sirtuins. It has anti-inflammator, anti-proliferative and apoptotic effects, mainly inhibiting growth of a number of cancer cell lines. In our study, we demonstrate a beneficial effect of sirtinol as an anti-ageing agent, mainly by reversing muscle ageing. Publication: Deacetylation Inhibition Reverses PABPN1-Dependent Muscle Wasting: DOI: 10.1016/j.isci.2019.01.024 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2019
Development Status Actively seeking support
Impact Sirtinol is currently considered as an anti-ageing agent in the clinic.