Understanding targeted protein degradation for design of optimized therapeutic strategies

自2015年以来，一种新型的治疗分子已经撼动了药物发现。传统的方法依赖于发现药物，这种药物结合到导致疾病的“无赖”蛋白质上，并关闭它们的活性。这些所谓的抑制药物与它们的目标紧密结合，以关闭它们，并且它们需要在高剂量下永久存在，以保持流氓蛋白的不活跃。可以与细胞蛋白质降解机制的元件结合的分子的发现，开启了一种全新治疗模式的可能性。通过将抑制物连接到招募蛋白质降解机制的分子而产生的双功能化合物可以导致对流氓蛋白质的完全破坏。这种方法已被证明在消除一些治疗靶点方面有效，目前正在进行临床试验，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。这种方法的一大优点是，药物不再需要一直存在以永久阻止其靶标：由于单个结合事件可以破坏目标蛋白，这些药物的使用剂量可以比传统药物低得多，副作用也可能更少。尽管这些双功能分子的治疗可能性产生了兴奋，但我们仍然不知道它们是如何发挥作用的--因此，什么是成功的药物。因此，破译这些双功能分子(被广泛称为PROTAC)作用的生物学基础，将是设计未来战略的关键，这些战略考虑到哪些蛋白质可以被降解，什么类型的药物可以降解，以及是否有可以修改的额外参数来提高靶标销毁的效率。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)，它被认为是癌症中的一个无赖角色，也是抗癌药物开发中最受欢迎的靶点。我们最近发现了一种能降解AURKA的PROTAC，并建议使用这种PROTAC，以及我们对AURKA细胞属性和行为的广泛了解，来揭示调节AURKA活性的一些亚细胞参数。我们的目标是确定影响PROTAC活性的参数，既有优化AURKA靶向降解的具体特征，也有这类药物的一般特征。我们将测试其他PROTAC目标的降解(与AURKA具有重叠和不同的特性)，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活动的一般和特定规则。

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.