Understanding targeted protein degradation for design of optimized therapeutic strategies

了解靶向蛋白质降解以设计优化的治疗策略

• 批准号: BB/X007499/1
• 负责人: Catherine Lindon
• 金额: $ 56.46万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX007499%2F1
• 关键词: Understanding; targeted; protein; degradation; design

A new type of therapeutic molecule has shaken up drug discovery since 2015. Traditional approaches have relied on discovering drugs that bind to 'rogue' proteins that cause disease and switch off their activity. These so-called inhibitor drugs bind tightly to their target to switch them off, and they need to be permanently present at high doses to keep the rogue protein inactive. The discovery of molecules that can bind to elements of the protein degradation machinery of the cell has opened up the possibility of a new mode of therapy altogether. Bifunctional compounds created by linking an inhibitor to a molecule that recruits protein degradation machinery can lead to complete destruction of the rogue protein. This approach has been shown to work in eliminating a number of therapeutic targets and is now in clinical trials as a potential treatment for prostate cancer (through destruction of the Androgen Receptor) and other diseases. One great advantage of this approach is that a drug no longer needs to be present at all times to keep its target blocked permanently: Since a single binding event can destroy the target protein, these drugs can be used at much lower doses than conventional drugs and may have fewer side-effects.Despite the excitement generated by the therapeutic possibilities of these bifunctional molecules, there is still a lot that we don't understand about how they work - and therefore about what makes a successful drug. Deciphering the biology that underlies the action of these bifunctional molecules, widely referred to as 'PROTACs', will therefore be key to designing future strategies that take into account which proteins can be degraded and by what type of drug, and whether there are additional parameters that can be modified to enhance the efficiency of target destruction. Our lab has spent 10 years researching an important cellular protein, Aurora kinase A (AURKA), known to be one rogue player in cancer, and a favourite target in cancer drug development. We have recently discovered a PROTAC that works to degrade AURKA, and propose to use this PROTAC, and our extensive knowledge of the cellular properties and behaviour of AURKA, to uncover some of the subcellular parameters that regulate its activity. We aim to identify parameters contributing to PROTAC activity, both specific features that will optimize targeted degradation of AURKA and general features of this class of drug. We will test degradation of additional PROTAC targets (with overlapping and distinct properties to AURKA), and alternative degradation tools against AURKA (that harness different bits of the cellular degradation machinery) to establish the general and specific rules of PROTAC activity.

自2015年以来，一种新型的治疗分子已经动摇了药物发现。传统的方法依赖于发现与导致疾病的“流氓”蛋白质结合并关闭其活性的药物。这些所谓的抑制剂药物与它们的靶标紧密结合以关闭它们，并且它们需要以高剂量永久存在以保持流氓蛋白质不活跃。能够与细胞蛋白质降解机制的元件结合的分子的发现，为全新的治疗模式开辟了可能性。通过将抑制剂与招募蛋白质降解机制的分子连接而产生的双功能化合物可以导致流氓蛋白质的完全破坏。这种方法已被证明可以消除许多治疗靶点，目前正在临床试验中作为前列腺癌（通过破坏雄激素受体）和其他疾病的潜在治疗方法。这种方法的一个巨大优势是，药物不再需要一直存在才能永久阻止其靶点：由于单个结合事件可以破坏靶蛋白，因此这些药物可以以比常规药物低得多的剂量使用，并且可能具有更少的副作用。尽管这些双功能分子的治疗可能性引起了兴奋，关于它们是如何工作的，我们还有很多不了解的地方，因此也就不知道是什么造就了一种成功的药物。因此，破译这些被广泛称为“PROTAC”的双功能分子的作用基础的生物学将是设计未来策略的关键，这些策略将考虑哪些蛋白质可以被降解以及被什么类型的药物降解，以及是否有其他参数可以被修改以提高靶点破坏的效率。我们的实验室花了10年的时间研究一种重要的细胞蛋白，极光激酶A（AURKA），已知它是癌症中的一个流氓球员，也是癌症药物开发中最受欢迎的目标。我们最近发现了一种PROTAC，它可以降解AURKA，并建议使用这种PROTAC，以及我们对AURKA细胞特性和行为的广泛了解，来揭示一些调节其活性的亚细胞参数。我们的目标是确定有助于PROTAC活性的参数，包括优化AURKA靶向降解的具体特征和这类药物的一般特征。我们将测试其他PROTAC靶标（与AURKA具有重叠和不同的特性）的降解，以及针对AURKA的替代降解工具（利用细胞降解机制的不同部分），以建立PROTAC活性的一般和特定规则。