Production of Niraparib using Imine Reductases

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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.