ANCHOR E3s · Anchoring ligandable binding sites at E3 ligase surfaces for plug-and-play PROTACs.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-08-01 → 2018-07-31
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Anchoring ligandable binding sites at E3 ligase surfaces for plug-and-play PROTACs.
Many human diseases, including cancer, are often characterised by the malfunctioning or misregulation of specific proteins. A general therapeutic approach to improve the health of diagnosed patients is to use chemical compounds that bind to the active site of the protein and inhibit its action. In our research group we tackle the problem from a different perspective by developing so-called PROteolysis-TArgeting Chimera (PROTAC) compounds. These molecules bind a protein of interest that we aim to destroy and an E3 ubiquitin ligase, which targets proteins for degradation within the body. To summarise, PROTACs hijack the natural functioning of the cellular machinery to trigger selective degradation of the protein of interest. Since PROTACs do not require binding to a functional site of the protein, there is mounting expectation regarding their use to treat currently challenging pharmacological disorders, such as specific cancer types. The current project focusses on developing computational tools to discover novel binding sites in proteins, and to use molecular modelling tools to study different aspects of PROTAC design and mode of action. This is important to ensure that the technology reaches the desired levels of usability and to expand its applicability scope. Notably, the first targeted protein degraders are expected to enter oncology clinical phase I studies by the end of 2018.
Data: CORDIS, © European Union
Project objective
The Anchor E3s project proposes to establish, for the first time, an efficient protocol for the discovery and characterisation of accessible binding sites at any patch of a protein surface, regardless of its involvement in biological function. One of the motivation of the research is to develop a general approach to discover new “anchor” ligands that can enable improved plug-and-play proteolysis targeting chimeras (PROTACs) as chemical degraders of any protein of interest. The project will build on results from the host lab who identified a series of low molecular-weight fragments addressing novel patches at the surface of Cullin RING E3 ubiquitin ligases (CRLs) with currently unknown functionality, demonstrating that accessible and “ligandable” binding sites can be found on CRL surfaces. A combination of structure-based computational techniques informed by biophysical experiments and X-ray crystallography will be used to reveal, characterise, and target new ligandable binding sites at CRL surfaces. Promising anchor fragments will then be identified and grown into suitable binders, and eventually linked to assemble novel PROTACs, which will be assessed in cellular assays. The ultimate goal of the research is to develop and establish the PROTAC approach as an efficient and universal chemical biology platform for target validation, regardless of the perceived “druggability” of the targeted protein.
Original text from CORDIS.
Participants
- UNIVERSITY OF DUNDEE · DundeeCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union