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

在英国，每天有1000个新的癌症病例，450人死于癌症。45%的患者接受手术切除肿瘤。尽管自2011年以来批准了97种新的精准药物治疗方法，但只有8%的癌症患者可以通过这些精准药物治疗。这些统计数据突出表明，有真实的需要为相当大比例的癌症开发安全、广谱的治疗方法。癌症的一个特征是能够快速、持续和不受控制地生长。癌症通常通过将我们自己细胞的蛋白质合成机制置于细胞内来实现这一点。我们细胞中的蛋白质是由一种叫做核糖体的复合体从各个部分组合在一起的。癌症利用这一点，通过创造额外的核糖体复合物，允许不可控的蛋白质合成和癌细胞生长。它通过增加控制核糖体构建的蛋白质复合物的生产力来实现这一点，该复合物称为RNA聚合酶I（通常称为Pol I）。我们已经使用的许多治疗癌症的药物都关闭了Pol I，所以我们知道这是一个很好的药物靶点。然而，我们已经使用的药物并不特定，所以它们也会击中许多其他重要的目标，给我们带来副作用。在这项研究中，我们将制造一种只能关闭Pol I的化合物，为我们提供一种副作用大大减少的高效药物。因为Pol I在几乎所有的癌症中都能找到，所以这种药物几乎能控制所有的癌症，是一种广谱的癌症治疗药物。Pol I复合物是十四种蛋白质的集合，通常在负责发育的细胞中非常活跃。随着年龄的增长，Pol I会减慢，因此在正常健康的细胞中，Pol I的活性非常低。这意味着，如果我们能够制造出关闭成年人Pol I的化合物，那么它只会影响已经打开Pol I的癌细胞，而不会影响我们的健康细胞。一些发育障碍有DNA突变，导致Pol I在我们发育过程中被关闭。患有发育障碍的人在最需要的时候表现出非常低的Pol I活性。这表明，发育障碍患者DNA中的突变掌握着我们如何在癌症中关闭Pol I的秘密。我们从一种疾病（发育障碍）中学到的知识将使我们能够选择性地治疗另一种疾病（癌症）。两年多来，该项目旨在找到控制Pol I复合物中蛋白质相互作用的分子。蛋白质-蛋白质相互作用控制许多疾病，但对药物的影响具有挑战性。蛋白质是大分子，而药物是小分子，就像一只奇瓦瓦州试图把相扑选手分开。该项目将使用我们研究小组开发的一种新技术来制造控制Pol I蛋白质-蛋白质相互作用的分子。首先，多肽，一种看起来和作用都像人造相扑手手臂的小蛋白质分子，将通过复制天然蛋白质结构来制造。使用肽作为支架，可以用药物片段代替部分来制造药物分子。工作将集中在为此目的设计分子，并将其开发为良好的精准医学先导。这些新分子将打破Pol I复合物，阻止癌细胞不受控制地生长，并提供广谱工具来研究癌症中蛋白质合成的控制。该项目将建立在我们小组以前的研究基础上，该研究确定了能够控制蛋白质-蛋白质相互作用的药物样化合物。我们将研究新的方法来提高这一过程的速度和效率，以便可以识别任何感兴趣的蛋白质相互作用的化学工具。

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.