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

在英国，每天有1000例新的癌症病例和450例癌症死亡。45%的患者接受手术切除肿瘤。尽管自2011年以来，有97种新的精准药物疗法获得批准，但只有8%的患者可以通过这些精准药物治疗癌症。这些统计数据突出表明，确实需要开发安全、广谱的治疗方法来治疗大部分癌症。癌症的一个特点是能够快速、持续和不受控制地生长。癌症通常是通过让我们自身细胞的蛋白质合成机器超负荷运转来实现这一目标的。我们细胞中的蛋白质是由一种叫做核糖体的复合体将部分蛋白质组合在一起的。癌症利用这一点，产生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目标，这种复合物被称为RNA聚合酶I（通常简称为Pol I）。我们已经用于治疗癌症的许多药物会关闭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具有特异性，因此它们也会击中许多其他重要目标，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，从而使我们获得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存在，这种药物将控制几乎所有的癌症，实现广谱的癌症治疗。Pol I复合体是14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的活性降低，因此在正常的健康细胞中，Pol I的活性非常低。这意味着，如果我们能制造出在成人体内关闭Pol I的化合物，它只会影响那些激活Pol I的癌细胞，而不会影响健康细胞。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Pol I的时候表现出非常低的活性。这表明，发育障碍患者的DNA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有选择地治疗另一种疾病（癌症）。在两年多的时间里，这个项目旨在找到控制Pol I复合物中蛋白质相互作用的分子。蛋白质与蛋白质之间的相互作用控制着许多疾病，但对药物来说却是一个挑战。蛋白质是大分子，而药物是小分子，就像吉娃娃试图分开相扑手一样。这个项目将使用我们研究小组开发的一项新技术，来制造控制Pol i蛋白-蛋白相互作用的分子。首先，肽，一种看起来和行为都像人工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。利用多肽作为支架，切片可以被药物片段取代，从而形成药物分子。工作将集中于为此目的设计分子，并将其发展成为良好的精准医疗先导。这些新分子将分解Pol I复合物，阻止癌细胞不受控制地生长，并为研究癌症中蛋白质合成的控制提供了一种广谱工具。这个项目将建立在我们小组先前的研究基础上，该研究确定了能够控制蛋白质-蛋白质相互作用的类药物化合物。我们将研究新的方法来提高这一过程的速度和效率，以便化学工具可以识别任何感兴趣的蛋白质相互作用。

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.