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。传统方法依赖于发现与引起疾病并关闭其活性的“流氓”蛋白结合的药物。这些所谓的抑制剂与靶标紧密结合，将其关闭，并且需要高剂量地存在以保持流氓蛋白质不活跃。发现可以结合细胞蛋白质降解机制元素的分子的发现，已经打开了一种新的治疗方式。通过将抑制剂与募集蛋白质降解机械募集的分子联系起来而产生的双功能化合物可能会导致流氓蛋白质的完全破坏。已证明这种方法可以消除许多治疗靶标，现在正在临床试验中作为前列腺癌的潜在治疗方法（通过雄激素受体的破坏）和其他疾病。这种方法的一个很大的优势是，不再需要始终存在一种药物才能永久阻止其目标：由于单个约束事件可以破坏目标蛋白质，因此可以比传统药物低得多的剂量使用这些药物，并且可能较少具有较少的副作用。 药品。因此，将这些双功能分子的作用（广泛称为“ Protacs”）的作用的生物学解释为设计将是设计未来策略的关键，这些策略要考虑到哪些蛋白质可以降解，以及是否可以通过哪些类型的药物进行降解，以及是否有其他参数可以修改以提高目标目标销毁的效率。我们的实验室花了10年的时间研究了重要的细胞蛋白Aurora激酶A（Aurka），该蛋白是癌症中的一名流氓玩家，并且是癌症药物开发中最喜欢的靶标。我们最近发现了一种旨在降解Aurka的Protac，并建议使用此Protac，以及我们对Aurka细胞特性和行为的广泛了解，以发现一些调节其活性的亚细胞参数。我们旨在确定有助于Protac活性的参数，这两个特定特征都可以优化Aurka的靶向降解和此类药物的一般特征。我们将测试其他Protac靶标（具有重叠和不同特性的Aurka）的降解，以及针对Aurka的替代降解工具（该降解工具（该工具都利用了细胞降解机制的不同位），以建立Protac活性的一般和特定规则。