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.

发现超过70％的所有癌症的人类基因被称为MYC至关重要。该基因编码蛋白质（称为CMYC），该蛋白质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，因为它存在于抗体无法进行的癌细胞核内。 CMYC也是一种很难用小分子药物靶向的蛋白质，可以进入癌细胞的细胞核，但不能轻易阻止CMYC与其他蛋白质和DNA的大型表面区域之间产生的相互作用。众所周知，没有小分子可以阻止CMYC蛋白质相互作用，并且只有少数非常低效力的小分子阻止了myc-DNA相互作用。在这里，我们将开发和测试一种新方法来产生疗法，从长远来看，可以通过沉默CMYC来克服这些问题并杀死MyC的癌细胞而无需杀死正常的人类细胞。我们建议在细胞内部筛选含氨基酸的肽的文库，以找到具有选择性结合与CMYC的最佳能力的库。我们已经开发了一种方法，可以通过添加化学“电力剂”来拧紧肽与靶蛋白的结合，该化学“电力”将肽粘贴到蛋白质上，例如安全销机制。优化的肽将有选择地与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。 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与蛋白质CMYC的不可逆结合，（c）最大程度地吸收了肽对癌细胞的摄取并进一步摄取其核，（d）（d）与CMYC在癌细胞核内的不可逆结合，（e）诱导一系列CMYC表达人类癌细胞的死亡，而无需杀死正常细胞。在这些努力中的成功将使制药公司和医学研究人员对CMYC感到兴奋，这将引起极大的兴趣。我们为一个非常有希望的新癌症靶标提供了一种全新且可行的治疗方法。开发的技术可能可以转移到与疾病途径有关的其他蛋白质蛋白质相互作用（PPI）。