Expanding the Functionality and Target Spectrum of Kinase Inhibitors using PROTACs

使用 PROTAC 扩展激酶抑制剂的功能和靶谱

• 批准号: 496561415
• 负责人: Professor Dr. Stefan Knapp
• 金额: --
• 依托单位: Institut für Pharmazeutische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/496561415?language=en
• 关键词: Expanding; Functionality; Target; Spectrum; Kinase

Kinase inhibitors are widely used drugs that have significantly improved the prognosis of cancer patients. However, many kinases or kinase-related proteins remain to be targeted, as inhibitors did not meet the expectations raised by genetic experiments or they have been associated with intolerable toxicity. An example where conventional inhibition of a kinase by ATP competitive inhibitors has not led to clinical success so far is the Aurora-A kinase. Aurora-A plays a central role in tumorigenesis and genetic data have demonstrated that many tumours critically depend on Aurora-A for growth, making this a compelling case for therapeutic targeting of Aurora-A in cancer. Unfortunately, all clinical trials with Aurora-A kinase inhibitors showed no significant therapeutic effect, but dose-limiting toxicity, and many trials have been terminated prematurely. Therefore, no Aurora-A-targeting drugs are currently available.As many reports indicate also a non-catalytic function of Aurora-A in tumour cells, we explored the inhibition of Aurora-A by a new class of small molecules called proteolysis targeting chimeras (PROTACs). Instead of inhibiting the catalytic activity, PROTACs recruit targets to cellular E3 ubiquitin ligases and thereby induce proteasomal degradation, thus also addressing non-catalytic protein functions. We recently developed a PROTAC that induced rapid and specific degradation of Aurora-A in leukaemia cells. Strikingly, this tool compound caused S phase arrest and rampant apoptosis, which is markedly different from the cellular effects of Aurora-A kinase inhibitors. While these results open a new avenue to target Aurora-A scaffolding function in cancer therapy, the developed PROTACs also provide a versatile tool to study Aurora-A function and its mediated interaction with signalling partners. Based on our preliminary data, we will now develop the Aurora-A PROTAC for in vivo use in mouse models to explore the potential of Aurora-A degradation in cancer therapy. We will improve the pharmacokinetics of the compound based on our model of the ternary Aurora-PROTAC-CEREBLON complex. We will use this optimized PROTAC to explore the efficacy and safety Aurora-A PROTACs in pre-clinical leukaemia models. At the same time, we will use our compounds to obtain a better understanding of the scaffolding role of Aurora-A regulating the cell cycle.In a second line of experiments, we will develop PROTACs for the promising cancer targets RUVBL1 and RUVB2. As Aurora-A, RUVBL proteins directly bind the onco-protein MYC and are indispensable for MYC´s oncogenic function. Moreover, and again similar to Aurora-A, both proteins bind and hydrolyse ATP, but have additional important oncogenic functions that are independent from their catalytic activity. Building on our experience with Aurora-A PROTACs, we will design, synthesize and characterize RUVBL1/2 PROTACs and test their anti-cancer properties in leukaemia models.

激酶抑制剂是广泛使用的药物，显著改善了癌症患者的预后。然而，许多激酶或激酶相关蛋白仍然是靶向的，因为抑制剂不符合遗传实验提出的期望，或者它们与不可耐受的毒性有关。迄今为止，ATP竞争性抑制剂对激酶的常规抑制尚未导致临床成功的实例是Aurora-A激酶。Aurora-A在肿瘤发生中起着核心作用，遗传数据表明，许多肿瘤的生长严重依赖于Aurora-A，这使得Aurora-A在癌症中的治疗靶向成为一个令人信服的案例。不幸的是，所有Aurora-A激酶抑制剂的临床试验都没有显示出显著的治疗效果，而是剂量限制性毒性，许多试验已经提前终止。由于许多报告表明Aurora-A在肿瘤细胞中也具有非催化功能，因此我们探索了一类称为蛋白水解靶向嵌合体（PROTAC）的新型小分子对Aurora-A的抑制作用。PROTAC不是抑制催化活性，而是将靶标募集到细胞E3泛素连接酶，从而诱导蛋白酶体降解，因此也解决了非催化蛋白质功能。我们最近开发了一种PROTAC，可诱导白血病细胞中Aurora-A的快速特异性降解。引人注目的是，这种工具化合物引起S期阻滞和猖獗的细胞凋亡，这与Aurora-A激酶抑制剂的细胞效应明显不同。虽然这些结果为靶向癌症治疗中的Aurora-A支架功能开辟了一条新途径，但开发的PROTAC也为研究Aurora-A功能及其与信号伴侣的介导相互作用提供了一种通用工具。基于我们的初步数据，我们现在将开发Aurora-A PROTAC用于小鼠模型的体内使用，以探索Aurora-A降解在癌症治疗中的潜力。我们将基于我们的三元Aurora-PROTAC-CEREBLON复合物模型改善该化合物的药代动力学。我们将使用这种优化的PROTAC来探索Aurora-A PROTAC在临床前白血病模型中的有效性和安全性。同时，我们将使用我们的化合物来更好地理解Aurora-A调节细胞周期的支架作用。在第二系列实验中，我们将开发用于有前途的癌症靶点RUVB 1和RUVB 2的PROTAC。与Aurora-A一样，RUVBL蛋白直接结合癌蛋白MYC，是MYC致癌功能不可或缺的。此外，与Aurora-A类似，这两种蛋白质都结合并水解ATP，但具有独立于其催化活性的额外重要致癌功能。基于我们在Aurora-A PROTAC方面的经验，我们将设计、合成和表征RUVBL 1/2 PROTAC，并在白血病模型中测试其抗癌特性。