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.

该提案旨在开发多酶合成途径，向PARP抑制剂的关键中间体-Niraparib（一种用于治疗卵巢癌的药物）。最初的结果表明，我们的酶促方法的可行性，但也强调了酶促活动的改进需要，以开发行业要求的有效综合。 GSK最近购买了Tesaro公司，并享有其药物分子-Niraparib的权利。当前通往中间体的合成途径最初是由默克公司开发的，涉及八步合成。通过我们提出的途径，这将减少到访问同一中间体的五个步骤，降低了合成途径的复杂性将改善最终药物分子传递的交货时间。此外，该项目中提出的途径还避免了默克合成途径所需的二氯化铝介导的弗里德尔工艺酰基化的使用。该项目中的主要目标是改善IRED和HDNO酶的活动。因此，Turner组先前从事过的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在此过程中适合其目的。还需要对Meta-Eir-358进行设计，以增加其对本应用程序中定义的底物的特定活动。此外，这两个酶都需要在所需的过程条件下进行设计。 GSK最近发表了一篇具有里程碑意义的论文，他们在其中设计了一个IRED，以减少胺化，既有改善的底物负荷，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-Eir-358，我们将寻求增强这两种酶的热稳定性，溶剂和pH耐受性。一旦酶进行了设计，我们将与GSK合作开发可在试点规模上使用的过程。