Substrate Peptidomimetic Inhibitors (SPIs) of the COP9 signalosome
Lead Research Organisation:
University of Oxford
Department Name: Target Discovery Institute
Abstract
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.
Publications
Archibald LJ
(2022)
Hydroxamic Acid-Modified Peptide Library Provides Insights into the Molecular Basis for the Substrate Selectivity of HDAC Corepressor Complexes.
in ACS chemical biology
Chen Z
(2022)
Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation.
in Cell death and differentiation
Clancy A
(2021)
Correction: The deubiquitylase USP9X controls ribosomal stalling.
in The Journal of cell biology
Clancy A
(2021)
The deubiquitylase USP9X controls ribosomal stalling.
in The Journal of cell biology
Damianou A
(2024)
Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex.
in Life science alliance
Davis S
(2023)
Deep topographic proteomics of a human brain tumour
in Nature Communications
| 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 |
| URL | http://gtr.rcuk.ac.uk/projects?ref=EP%2FN034295%2F1 |
| 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 | 03/2018 |
| End | 03/2021 |
| Description | Modulation of innate immune signalling pathways by the Ub/Ubl system and TCM products |
| Amount | £520,000 (GBP) |
| Funding ID | 2018-I2M-2-002 |
| Organisation | Academy of Medicine |
| Sector | Academic/University |
| Country | Singapore |
| Start | 01/2020 |
| End | 12/2024 |
| 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 |
| URL | https://www.cell.com/iscience/fulltext/S2589-0042(19)30025-2?_returnURL=https%3A%2F%2Flinkinghub.els... |
| 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 | Oxford-BMS Alliance 2024-2026 |
| Organisation | Bristol-Myers Squibb |
| Country | United States |
| Sector | Private |
| PI Contribution | The Oxford-Bristol Myers Squibb alliance was established in 2015 through our Translational Fellowship Programme, with the aim of stimulating new scientific discovery and translation and to generate a cohort of scientists that can navigate within and across both academic and industry spheres to bridge translational challenges. Oxford's alliance with Bristol Myers Squibb continues to grow year on year, the total of Oxford-Bristol Myers Squibb Fellows is now 37 and many other collaborative projects are currently running. Collaborative work with BMS involved the biochemical characterisation of small molecule inhibitors of ubiquitin specific protease 30 (USP30), a promising target for the treatment of Parkinson's Disease. |
| Collaborator Contribution | In my team, a postdoctoral fellow, Dr Hannah Jones, will continue work on discovering novel biomarkers related to the Parkinson's Disease target ubiquitin specific protease 30 (USP30), particularly reporting on the efficacy of interfering with USP30 activity in the brain using brain-penetrant small molecule USP30 inhibitors. |
| Impact | Advanced small molecules targeting USP30 as a novel target in Parkinson's disease, establishing a clinical candidate molecule Ongoing drug discovery programme with BMS and Evotec |
| Start Year | 2024 |
| 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. |
| URL | https://www.ncbi.nlm.nih.gov/pubmed/?term=kessler+bm+olie+c |