Periodic Reporting for period 1 - DELETER (DCAF E3 Ligase Exploration To Expand degRadation)
Periodo di rendicontazione: 2021-05-01 al 2023-04-30
Targeted protein degradation (TPD) is emerging as a new way to treat diseases that works differently from traditional therapies and has several advantages. Instead of inhibiting a protein by binding to it and preventing it from functioning, TPD hijacks protein degradation pathways, such as the ubiquitin-proteasome system, that naturally exist in our cells to completely destroy dangerous proteins associated with diseases such as cancer. Complete removal of a protein from the cells disrupts all of it's potentional functions, potentially leading to a bigger impact than just inhibiting one function with a traditional drug. TPD also has the potential to expand druggable space, in that it can target "undruggable" proteins that are of high therapeutic interest but have proven resistant to targeting with conventional drugs. The TPD approach could also improve precision of therapies, targeting only diseased tissue and minimising side effects and damage to healthy tissue. There are two main types of molecules that are used in TPD: molecular glues and Proteolysis Targeting Chimeras (PROTACs). Both of these molecules work by sticking two proteins together, causing one protein, called the ligase, to tag the other protein (the target) with a molecule called ubiquitin. The ubiquitin tag is recognised by the cells garbage disposal system called the proteasome, which destroys the target protein.
Beyond disease therapy, TPD can also be used as a tool to help us understand normal and disease functions of proteins by removing them from healthy or diseased cells and looking at the consequences.
In order to advance TPD and enhance its prospects for creating treatments for diseases, we are exploring different components of the protein degradation pathway known as the ubiquitin-proteasome system to better understand how they work. We also hope to find small molecule drugs that can manipulate this pathway for therapeutic benefits.
Beyond disease therapy, TPD can also be used as a tool to help us understand normal and disease functions of proteins by removing them from healthy or diseased cells and looking at the consequences.
In order to advance TPD and enhance its prospects for creating treatments for diseases, we are exploring different components of the protein degradation pathway known as the ubiquitin-proteasome system to better understand how they work. We also hope to find small molecule drugs that can manipulate this pathway for therapeutic benefits.
The project involves making large quantities of protein components involved in ubiquitin-proteasome system to investigate their structure and function, and to search for drug molecules that bind to them. To date, I have made several of these proteins and am currently investigating their structure and function.
One of these proteins has been explored in more details with a large group of collaborators. We have recently put up a pre-print article on Biorxiv looking at one of this protein, DCAF16, and how it is recruited by a drug to tag another protein, BRD4, for destruction. In the work, I determined the atomic structure of the complex formed between DCAF16, the drug molecule and BRD4. We found that the drug works by a novel mechanism we termed "intramolecularly bivalent gluing", whereby it binds to two parts of BRD4 and glues it to DCAF16. This new mechanism and the previously unknown structure of DCAF16 will inform future efforts to exploit proteins like DCAF16 for TPD therapies.
One of these proteins has been explored in more details with a large group of collaborators. We have recently put up a pre-print article on Biorxiv looking at one of this protein, DCAF16, and how it is recruited by a drug to tag another protein, BRD4, for destruction. In the work, I determined the atomic structure of the complex formed between DCAF16, the drug molecule and BRD4. We found that the drug works by a novel mechanism we termed "intramolecularly bivalent gluing", whereby it binds to two parts of BRD4 and glues it to DCAF16. This new mechanism and the previously unknown structure of DCAF16 will inform future efforts to exploit proteins like DCAF16 for TPD therapies.
Currently only a small number of components of protein degradation pathways have been used for TPD. My work will expand our drug discovery toolbox, increase our understanding of the pathways involved and hopefully lead to new drugs to treat diseases. The results produced so far enhance our understanding of a previously poorly characterised protein DCAF16 and pave the way for its use in TPD. They also describe a novel way to stick two proteins together by intramolecularly bivalent gluing, a strategy that could help to destroy traditionally difficult to target proteins by TPD.