Production of Niraparib using Imine Reductases

使用亚胺还原酶生产尼拉帕尼

• 批准号: BB/V003410/1
• 负责人: Nicholas Turner
• 金额: $ 24.83万
• 依托单位: University of Manchester
• 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=BB%2FV003410%2F1
• 关键词: Production; Niraparib; using; Imine; Reductases

This proposal aims to develop a multi enzymatic synthetic route to a key intermediate of the PARP inhibitor (S)-niraparib, a drug used to treat ovarian cancer. Initial results have demonstrated the feasibility of our enzymatic approach but also highlighted the need for improvement in the enzymatic activities in order to develop an efficient synthesis required by industry. GSK recently purchased the company Tesaro and with it the rights to their drug molecule (S)-niraparib. The current synthetic route to the intermediate was initially developed by Merck and involves an eight step synthesis. With our proposed route this would be reduced to just five steps to access the same intermediate, this reduction in complexity of the synthetic route would improve lead times for the delivery of the final drug molecule. Additionally, the route proposed within this project also avoids the use of aluminium trichloride mediated Friedel-Crafts acylation required by the Merck Synthetic route. The key objectives within this project will be to improve the activities of the IRED and HDNO enzyme involved. The HDNO enzyme, previously worked on by the Turner group, was optimised for alternative model substrates therefore will require re-engineering to ensure that it is fit for purpose within this process. The meta-IRED-358 will also need to be engineered to increase its specific activity towards the substrates defined within this application. In addition, both enzymes will need to be engineered to work in the desired process conditions. GSK have recently published a landmark paper in which they engineered an IRED for reductive amination with both improved substrate loading, low pH tolerance and enhanced thermostability. By applying the same techniques to our meta-IRED-358 we will look to enhance the thermostability, solvent and pH tolerance of both enzymes. Once the enzymes have been engineered we will work with GSK to develop a process that can be used at pilot scale.

该提案旨在开发一种多酶合成途径，以合成PARP抑制剂(S)-niraparib的关键中间体，这是一种用于治疗卵巢癌的药物。初步结果证明了我们的酶促方法的可行性，但也强调了改善酶活性的必要性，以便开发工业所需的高效合成。葛兰素史克最近收购了Tesaro公司，并获得了其药物分子(S)-niraparib的专利权。目前的中间体合成路线最初是由默克公司开发的，包括八个步骤的合成。通过我们提出的路线，这将减少到只有五个步骤来获得相同的中间体，这种合成路线复杂性的降低将缩短最终药物分子交付的交货时间。此外，本项目提出的路线还避免了默克合成路线所需的三氯化铝介导的Friedel-Crafts酰化的使用。该项目的主要目标是提高所涉及的IRED和HDNO酶的活性。先前由Turner小组研究的HDNO酶已针对替代模型底物进行了优化，因此需要重新设计以确保其适合该过程中的目的。还需要对meta-IRED-358进行设计，以增加其对本应用程序中定义的底物的特异性活性。此外，这两种酶都需要在所需的工艺条件下工作。GSK最近发表了一篇具有里程碑意义的论文，其中他们设计了一种用于还原性胺化的IRED，该IRED具有改进的底物负载、低pH耐受性和增强的热稳定性。通过将相同的技术应用于我们的meta-IRED-358，我们将寻求提高这两种酶的热稳定性，溶剂和pH耐受性。一旦酶被设计出来，我们将与GSK合作开发一种可用于中试规模的工艺。