Inhibiting RNA polymerase I by targeting the RPAC1/RPAC2 protein interaction highlighted by developmental disorders

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In the UK there are one thousand new cancer cases each day and 450 cancer deaths. 45% of patients undergo surgery to remove tumours. Despite the approval of 97 new precision pharmaceutical treatments since 2011, only 8% of patients have cancer treatable by these precision medicines. These statistics highlight there is a real need to develop safe, broad-spectrum treatments for a substantial proportion of cancers. A feature of cancer is an ability to grow rapidly, continuously, and uncontrollably. Cancer commonly achieves this by putting our own cells' protein synthesis machinery into overdrive. The proteins in our cells are put together from parts by a complex called the ribosome. Cancer takes advantage of this by creating extra ribosome complexes, allowing for uncontrollable protein synthesis and cancer cell growth. It does this by increasing the productivity of the protein complex that controls ribosome building, the complex called RNA polymerase I (often just called Pol I). Many of the drugs that we already use to treat cancer turn off Pol I, so we know this is a good drug target. However, the drugs we already use are not specific, so they also hit many other important targets, giving us side effects. In this research we will make a compound that can only turn off Pol I, giving us a highly effective drug with far reduced side effects. Because Pol I is turned up in almost all cancers this drug will control almost all cancers, making a broad-spectrum cancer treatment.The Pol I complex, which is a collection of fourteenproteins, is normally very active in the cells responsible for development. As we age Pol I slows down, so in normal healthy cells Pol I has very low activity. This means that if we can make compounds that turn off Pol I in adults it will only affect cancer cells which have turned Pol I up, leaving our healthy cells alone. Some developmental disorders have DNA mutations that results in Pol I being turned off while we are developing. People with the developmental disorders show very low Pol I activity when it is needed most. This suggests that the mutations in the DNA of patients with developmental disorders hold the secret to how we can turn off Pol I in cancer. The knowledge we have learnt from one type of disease (developmental disorders) will allow us to selectively treat another disease (cancer).Over two years, this project aims to find molecules that control the interactions of the proteins in the Pol I complex. Protein-protein interactions control many diseases but are challenging for drugs to affect. Proteins are large molecules and drugs are small, like a Chihuahua trying to keep apart sumo-wrestlers. This project will use a new technique, developed in our research group, to make molecules that control the protein-protein interactions of Pol I. First, peptides, small protein like molecules that look and act like artificial sumo-wrestler arms, will be made by copying the natural protein structure. Using peptides as scaffolds, sections can be replaced with drug pieces to make a drug molecule. Work will focus on designing molecules for this purpose and developing them to be good precision medicine leads. These new molecules will break apart the Pol I complex, stopping cancer cells from growing uncontrollably and providing a broad-spectrum tools to investigate the control of protein synthesis in cancer.This project will build on previous research from our group that identifies drug-like compounds capable of controlling protein-protein interactions. We will investigate new methods to increase the speed and efficiency of this process so that chemical tools can be identified for any protein interaction of interest.