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Irreversibly Silencing Oncogenic Master-regulator cMyc Using Library-derived Electrophilic Helical Peptides

使用文库衍生的亲电螺旋肽不可逆地沉默致癌主调节因子 cMyc

基本信息

批准号：
MR/T028254/1
负责人：
Jody Mason
金额：
$ 84.21万
依托单位：
University of Bath
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT028254%2F1
关键词：
Irreversibly Silencing Oncogenic Master regulator

项目摘要

A human gene that has been found to be crucial in the development of over 70% of all cancers is known as MYC. This gene codes for a protein (called cMyc) that is responsible for transforming normal cells to cancer cells and promoting cancer cell growth and tumour formation. cMyc is a difficult protein to target with antibody-based drugs because it exists inside the nucleus of cancer cells where antibodies cannot go. cMyc is also a difficult protein to target with small molecule drugs that can enter the nucleus of cancer cells but cannot readily block the interactions cMyc makes across large surface areas with other proteins and DNA. No small molecules are known to block cMyc-protein interactions, and only a few small molecules of very low potency block Myc-DNA interactions.Here we will develop and test a new approach to generating therapeutics that can, in the long term, overcome these problems by silencing cMyc and kill Myc-expressing cancer cells without killing normal human cells. We propose to screen libraries of amino acid-containing peptides inside cells to find those with the best ability to selectively bind to cMyc. We have developed a method for tightening the binding of peptides to the target protein through adding a chemical 'electrophile' that sticks the peptide to the protein like a safety pin mechanism. Optimised peptides will bind selectively to cMyc and not come off. This approach can chemically silence cMyc and prevent it from promoting cancer. Our preliminary data demonstrates that this approach can work in that we have found that we can irreversibly bind peptides to cMyc and stop its binding to protein partners present inside cells, potentially silencing its functions and causing cancer cell death without killing normal cells.The proposal seeks to build upon our strong proof-of-concept pilot data to optimise the peptide sequences for: (a) selective binding to the protein cMyc, (b) tight and irreversible binding to the protein cMyc, (c) maximum uptake of the peptides into cancer cells and further into their nucleus, (d) irreversible binding to cMyc inside the nucleus of cancer cells, (e) inducing death of a range of cMyc-expressing human cancer cells without killing normal cells. Success in these endeavours will be of exceptional interest to pharmaceutical companies and medical researchers who are becoming excited about cMyc as a new target for cancer. We present an entirely new and viable therapeutic approach to a very promising new cancer target. The technology developed will be potentially transferable to other protein-protein interactions (PPIs) implicated in disease pathways.

一种人类基因被发现在超过70%的癌症的发展中至关重要，被称为MYC。该基因编码一种蛋白质（称为cMyc），负责将正常细胞转化为癌细胞并促进癌细胞生长和肿瘤形成。cMyc是一种很难用基于抗体的药物靶向的蛋白质，因为它存在于癌细胞的细胞核内，而抗体不能进入。cMyc也是一种难以用小分子药物靶向的蛋白质，这些小分子药物可以进入癌细胞的细胞核，但不能容易地阻断cMyc与其他蛋白质和DNA在大表面积上的相互作用。目前还没有小分子能够阻断cMyc-蛋白质相互作用，只有极少数效力极低的小分子能够阻断Myc-DNA相互作用。在此，我们将开发并测试一种新的治疗方法，从长远来看，这种方法可以通过沉默cMyc来克服这些问题，并在不杀死正常人类细胞的情况下杀死表达Myc的癌细胞。我们建议筛选细胞内含有氨基酸的肽库，以找到那些具有选择性结合cMyc的最佳能力的肽。我们已经开发了一种方法，通过添加化学“亲电体”将肽粘附到蛋白质上，就像安全针机制一样，来加强肽与靶蛋白的结合。优化的肽将选择性地与cMyc结合而不会脱落。这种方法可以化学沉默cMyc并防止其促进癌症。我们的初步数据表明，这种方法可以工作，因为我们已经发现，我们可以不可逆地将肽与cMyc结合，并阻止其与细胞内存在的蛋白质伴侣结合，可能使其功能沉默，并导致癌细胞死亡，而不杀死正常细胞。该提案旨在建立在我们强大的概念验证试验数据的基础上，优化肽序列：（a）选择性结合cMyc蛋白，（B）紧密且不可逆地结合cMyc蛋白，（c）将肽最大限度地吸收到癌细胞中并进一步进入其细胞核，（d）不可逆地结合癌细胞核内的cMyc，（e）诱导一系列表达cMyc的人癌细胞死亡而不杀死正常细胞。这些努力的成功将引起制药公司和医学研究人员的极大兴趣，他们对cMyc作为癌症的新靶点感到兴奋。我们提出了一个全新的和可行的治疗方法，一个非常有前途的新的癌症靶点。开发的技术将有可能转移到疾病途径中涉及的其他蛋白质-蛋白质相互作用（PPI）。