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。蛋白质的翻译是由一个特定的信号终止，称为终止密码子。许多癌症在其基因中获得突变，导致RNA中过早的终止密码子，这意味着翻译的蛋白质比它们应该的要小，并且通常无法正常发挥功能。此外，含有提前终止密码子的RNA被认为是异常的，并被称为无义介导的衰变的质量控制过程破坏。过早的终止密码子和无义介导的衰变共同导致突变蛋白无法产生，这使得癌症失控。根据NHS的数据，鉴于此，英国每2个人中就有1人在一生中会患上某种形式的癌症，其中许多癌症是由肿瘤抑制基因中过早的终止密码子驱动的，至关重要的是，开发和探索克服过早终止密码子的新方法以获得其治疗潜力。位于邓迪的生物技术公司Tay Therapeutics（前身为In4Derm）已经创造出了高活性的小分子，这些小分子可以克服过早终止密码子，恢复全长功能性蛋白质的生产。这笔赠款将资助概念验证研究，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.