Exploiting read-through compounds as novel anticancer agents with a unique mechanism of action

为了让细胞产生蛋白质，包含我们基因的DNA被转录成RNA片段，然后由核糖体翻译成蛋白质。蛋白质的翻译被一个叫做终止密码子的特定信号终止。许多癌症的基因都发生了突变，导致RNA中的终止密码子过早产生，这意味着翻译的蛋白质比它们应有的尺寸要小，而且往往无法正常发挥作用。此外，含有过早终止密码子的RNA被认为是异常的，并被称为无意义介导的衰变的质量控制过程破坏。过早终止密码子和无义介导的衰变共同导致突变蛋白无法生成，从而使癌症失去控制。根据英国国家医疗服务体系（NHS）的数据，在英国，每2个人中就有1个人会在一生中患上某种形式的癌症，其中许多癌症是由肿瘤抑制基因中的过早终止密码子驱动的，因此开发和探索克服过早终止密码子的新方法并发掘其治疗潜力至关重要。Tay Therapeutics（前身为In4Derm）是一家位于邓迪的生物技术公司，他们已经创造出了高度活跃的小分子，可以克服过早停止密码子并恢复全长功能性蛋白质的生产。这笔拨款将用于概念验证研究，证明这种蛋白质的恢复足以杀死癌症。最终，我们设想这将导致一种强大的新方法来治疗各种癌症，使英国和世界各地的患者受益。

For cells to produce protein, the DNA that contain our genes, is transcribed into sections of RNA, which are then translated into protein by the ribosome. Translation of proteins is terminated by a specific signal called a stop codon. Many cancers have acquired mutations in their genes which result in premature stop codons in RNA, meaning that the translated proteins are smaller than they should be and are often unable to function properly. Additionally, RNA containing a premature stop codon is recognised as abnormal and destroyed by a quality control process known as nonsense-mediated decay. Together, premature stop codons and nonsense-mediated decay results in the mutated protein not being made, which enables a cancer to grow out of control.Given that, according to the NHS, 1 in 2 people in the UK will develop some form of cancer during their lifetime, many of which are driven by premature stop codons in tumour suppressor genes, it is vital that new ways to overcome premature stop codons are developed and explored for their therapeutic potential. Tay Therapeutics (formerly In4Derm), a biotech company based in Dundee, have created highly active small molecules that overcome premature stop codons and restore the production of full-length, functional protein.This grant will fund proof-of-concept studies that this restoration of protein is enough to kill cancers. Ultimately, we envision this will lead to a powerful new way to treat a wide variety of cancers to the benefit of patients in the UK and around the world.