TargetDUBs · Targeting ubiquitin processing in cancer and fibrosis: novel probes for the Ubiquitin Carboxy-Terminal Hydrolases
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-08-01 → 2021-08-14
- EU contribution
- €224,934
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Targeting ubiquitin processing in cancer and fibrosis: novel probes for the Ubiquitin Carboxy-Terminal Hydrolases
Ubiquitin specific peptidase 30 (USP30) is a member of the USP family of deubiquitinases (DUBs) and the only DUB present in mitochondria, where it deubiquitylates mitochondrial proteins and antagonizesmitophagy. USP30 overexpression is strongly associated with drug resistant lymphoma, leukaemia and multiple myeloma, in which apoptotic pathways are dysregulated through altered expression of BCL-2. USP30 depletion sensitizes cancer cells to BH3-mimetics (e.g. ABT-737), making it a potential target for cancer therapy, however, its endogenous substrates and regulation remain poorly understood. Similarly, Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) is a member of the UCH family of deubiquitinases (DUBs), and is the most abundant protein in the brain. UCHL1 dysregulation has been shown to be associated with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, various types of cancers (colorectal, breast, prostate, ovarian, and lung cancers), and liver fibrosis which could be related to lung and kidney fibrosis. While UCHL1 was shown to exert diverse Ub-associated activities (hydrolase, ligase, mono-Ub stabilizing), its actual functions, endogenous substrates, and how its activity is regulated in vivo, both in pathological and healthy tissues, remain poorly understood. To overcome these limitations, we planed to develop a USP30/UCHL1 activity-based probe (ABP) and apply them to the identification and quantification of USP enzyme activity and selective USP30/UCHL1 inhibitors in cancers and neurodegenerative diseases, using activity-based protein profiling.
Data: CORDIS, © European Union
Project objective
Modification of proteins with ubiquitin (Ub), itself a small protein, is a fundamental mechanism involved in regulation of almost all cellular functions. There are hundreds of enzymes involved in the addition or removal of Ub, and this system has emerged as an important drug target in many diseases. Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) is a member of the UCH family of deubiquitinases (DUBs), and is the most abundant protein in the brain. UCHL1 dysregulation has been shown to be associated with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, various types of cancers (colorectal, breast, prostate, ovarian, and lung cancers), and liver fibrosis. However, its actual functions, endogenous substrates, and how its activity is regulated in vivo, both in pathological and healthy tissues, remain poorly understood. To overcome these limitations and to realize the unmet therapeutic opportunities, I will develop and synthesize activity-based probes to selectively target UCHL1, and will apply them to the identification and quantification of UCH enzymes in several cancer cells using activity-based protein profiling. This will provide a unique tool to explore a wide range of DUBs and UCH biology in cells, as well as a starting point to develop selective inhibitors and potential therapeutics.Simultaneously, I will develop and synthesize irreversible PROTACs to selectively degrade UCHL1 and will apply them to quantitatively assess their effect on UCH enzymes in several in vitro cancer and fibrosis models using proteome-wide proteomics experiments. PROTACs are two-headed molecules capable to direct E3 ubiquitin ligase activity towards the target protein, driving its degradation by proteasome. I anticipate that novel PROTACs based on inhibitors that target UCHL1 would provide a unique tool to degrade UCHL1 and prevent deubiquitination, assisting discovery of novel UCHL1 substrates and providing a new paradigm for targeting UCHL1 in disease.
Original text from CORDIS.
Participants
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union