Production of Niraparib using Imine Reductases

该提案旨在开发PARP抑制剂（S）-Niraparib（一种用于治疗卵巢癌的药物）的关键中间体的多酶合成途径。初步结果已经证明了我们的酶促方法的可行性，但也强调了为了开发工业所需的有效合成，需要改进酶促活性。GSK最近收购了Tesaro公司，并获得了他们的药物分子（S）-Niraparib的权利。该中间体的当前合成路线最初由Merck开发，涉及八步合成。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改善最终药物分子递送的前置时间。此外，本项目中拟定的路线还避免了使用Merck合成路线所需的铝离子介导的Friedel-Crafts酰化。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。meta-IRED-358还需要被工程化以增加其对本申请中定义的底物的比活性。此外，这两种酶都需要经过工程改造，以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胺化的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，我们将寻求增强两种酶的热稳定性，溶剂和pH耐受性。一旦酶经过工程改造，我们将与葛兰素史克合作开发一种可以中试规模使用的工艺。

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.