Cancer drug discovery targeting the interaction of RAS oncogenic proteins with phosphoinositide 3-kinase

针对 RAS 致癌蛋白与磷酸肌醇 3-激酶相互作用的癌症药物发现

• 批准号: MR/W004054/1
• 负责人: Julian Downward
• 金额: $ 21.21万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW004054%2F1
• 关键词: Cancer; drug; discovery; targeting; interaction

It is estimated by Cancer Research UK that there are 17 million people developing cancer worldwide each year - which sadly causes 9.6 million death annually, making cancer one of the deadliest diseases of our time. Cancer remains a very challenging disease to cure despite the significant research effort that has been made through several decades. This is because cancer is a complex disease that is caused by multiple genetic mutations that occur in important cellular proteins - named oncogenic proteins. Oncogenic proteins are proteins that once mutated become hyperactive and causes several types of cancer. They contribute in the signaling and activation of several cellular pathways that are involved in cellular growth and proliferation. One of the major oncogenic protein families that causes almost 20% of human cancer is the RAS family of proteins. RAS proteins oscillate between two states, ON and OFF. The ON state of RAS interacts with several downstream enzymes to control cellular growth and proliferation. Oncogenic mutations in RAS lock it into the ON state, which causes constant and uncontrolled cellular growth and several types of cancers. Since the discovery of RAS protein in the 1980s, many efforts have been made to find inhibitors against oncogenic RAS. However, RAS proteins are challenging drug targets, despite the development of inhibitors that target one specific RAS mutation, G12C, which only represents 14% of total RAS oncogenic mutations. Therefore, applying new strategies that targets oncogenic-RAS mutants is an urgent requirement. Previous work in the Downward laboratory at the Francis Crick Institute (Crick) has established that blocking the interaction of RAS proteins with a particular downstream target enzyme named p110a inhibits tumour growth driven by RAS oncogenes in mice. Importantly blocking the KRAS/p110a interaction had no toxic effects in normal adult mice. These studies strongly support the idea that the complex of RAS with p110a protein may be an important drug target for future cancer therapies. Although these results are very encouraging, the nature of the weak RAS/p110a interaction makes it difficult to use available screening assays to discovery novel inhibitory chemicals which might be developed into drugs for treating cancers. We therefore initiated a collaboration with the pharmaceutical company AstraZeneca to develop a suitable screening assay for the RAS/p110a interaction. This was successfully achieved, resulting in a joint publication between the Crick and AstraZeneca in 2020. This secondment will strengthen our already successful collaboration with AstraZeneca and enable us to take the project to the next stage. I will apply the newly developed assay system to carry out high throughput screening of libraries of millions of chemical compounds to identify inhibitors that blocks RAS/p110a interaction. By combining expertise from two world class organisations - from academia, the Crick and from the pharmaceutical industry, AstraZeneca - we will maximise the chances of success for the project. Finding inhibitors that blocks the RAS/p110a interaction could lead the way to developing future treatments for all cancers driven by oncogenic RAS mutations, or around 20% of all human cancers.

据英国癌症研究所估计，全世界每年有1700万人患上癌症，每年导致960万人死亡，使癌症成为我们这个时代最致命的疾病之一。癌症仍然是一种非常具有挑战性的疾病，尽管几十年来已经进行了大量的研究工作。这是因为癌症是一种复杂的疾病，是由发生在重要细胞蛋白（称为致癌蛋白）中的多种基因突变引起的。致癌蛋白是一旦突变就变得过度活跃并导致几种类型癌症的蛋白质。它们有助于参与细胞生长和增殖的几种细胞途径的信号传导和激活。导致几乎20%的人类癌症的主要致癌蛋白家族之一是RAS蛋白家族。RAS蛋白在两种状态之间振荡，ON和OFF。RAS的ON状态与几种下游酶相互作用以控制细胞生长和增殖。RAS中的致癌突变将其锁定为ON状态，从而导致细胞持续且不受控制的生长和多种类型的癌症。自20世纪80年代RAS蛋白被发现以来，人们一直在寻找RAS的抑制剂。然而，RAS蛋白是具有挑战性的药物靶点，尽管针对一种特定RAS突变G12 C的抑制剂的开发，G12 C仅占总RAS致癌突变的14%。因此，应用靶向致癌RAS突变体的新策略是迫切需要的。之前在弗朗西斯克里克研究所（克里克）向下实验室的工作已经确定，阻断RAS蛋白与一种名为p110 a的特定下游靶酶的相互作用，可以抑制小鼠中由RAS癌基因驱动的肿瘤生长。重要的是，阻断KRAS/p110 a相互作用对正常成年小鼠没有毒性作用。这些研究有力地支持了RAS与p110 a蛋白的复合物可能是未来癌症治疗的重要药物靶点的想法。尽管这些结果非常令人鼓舞，但RAS/p110 a弱相互作用的性质使得难以使用可用的筛选测定来发现可能被开发成治疗癌症的药物的新型抑制性化学物质。因此，我们与制药公司阿斯利康（AstraZeneca）合作，开发一种适合RAS/p110 a相互作用的筛选方法。这一目标已成功实现，导致克里克和阿斯利康于2020年联合发表。这次借调将加强我们与阿斯利康已经成功的合作，并使我们能够将项目带入下一阶段。我将应用新开发的检测系统对数百万种化合物的文库进行高通量筛选，以鉴定阻断RAS/p110 a相互作用的抑制剂。通过结合来自两个世界级组织的专业知识-来自学术界的克里克和来自制药行业的阿斯利康-我们将最大限度地提高该项目的成功机会。找到阻断RAS/p110 a相互作用的抑制剂可能会为开发未来治疗所有由致癌RAS突变驱动的癌症（约占所有人类癌症的20%）的方法开辟道路。

项目成果

Characterisation of a cyclic peptide that blocks the RAS binding domain of phosphoinositide 3-kinase p110a

阻断磷酸肌醇 3-激酶 p110a RAS 结合域的环肽的表征

• DOI: 10.21203/rs.3.rs-1854923/v1
• 发表时间: 2022
• 作者: Ismail M