Periodic Reporting for period 1 - HETSPRESSO (A cartridge based flow chemistry machine for the automated synthesis of N-heterocycles for drug discovery)
Reporting period: 2016-11-01 to 2018-04-30
The development of new pharmaceuticals requires the iterative design and optimization of lead candidates through complex organic synthesis, which can be a major bottleneck in drug discovery. Given the rising costs of drug discovery and high attrition rates, there is increasing pressure to reduce timelines and invest in automated, time- and resource-efficient technologies that increase productivity. In order to reduce this bottleneck, our idea was to provide the technology and chemistry solutions needed to rapidly access lead structures – especially ones that will be better suited as drugs − in a safe, green, and cost effective manner.
Prior to the start of this project we had developed a flow-based prototype for the preparation of saturated N-heterocycles – an important structural class in drug discovery, which we nicknamed the “Hetspresso Machine”. Our key advance was the technology to immobilize heterocycle-forming reagents, based on the “SnAP reagents” that were developed in the course of an ERC StG. This new, immobilized reagent approach enabled the fabrication of disposable cartridges that delivered exactly the right amount of SnAP reagent for full conversion of an aldehyde substrate to the desired N-heterocycle. In addition, by using the flow-based prototype and disposable cartridges, all steps of the process could be carried out in a far safer manner since they occur in either the machine or the disposable cartridges. Productivity also had the potential to be enhanced because the fully automated process required no workup or purification, and took only a fraction of the “hands-on” time compared to the original SnAP process.
Although, prior to the initiation of this project, a few different “flavors” of SnAP cartridges had been tested, more studies and refinements to improve the scope were required. In addition, in order to simply the process for the user redesign of the cartridge was also required so that the four individual reagent cartridges used with the initial prototype could be integrated into a single cartridge. In order to incorporate the new cartridge design, some machine engineering optimization would also be required. ERC PoC funding was obtained to support these crucial developments and help achieve the ultimate goal of enabling a user to simply insert one of a range of different “flavors” of SnAP cartridge into the machine, and upon addition of the starting material, press a single button to start the whole automated process.
A portion of the ERC PoC funding was earmarked for the development and optimization of a single, disposable reagent cartridge system for use in the automated machine. A second part of the funding was allocated for the machine engineering optimization and construction of a fully operational, cartridge-based machine, which would serve as a demonstration model. A further portion of the funding was to be used to prepare a range of different “flavours” of N-heterocycle cartridges, which would allow us to fully determine the scope of the “Hetspresso Machine”. Finally, the remainder of the funding was assigned to support expansion of the concept to other reaction classes. Achievement of these four goals was crucial for the commercialization of this technology.
From the outset of the project, the aim was to redesign the cartridge and holder so that the four independent reagent cartridges that held the required immobilized reagents for the N-heterocycle forming process could be incorporated into a single, proprietary cartridge that could readily be loaded into the machine by a pressure-locking system or similar design. Based on customer feedback, we opted to pursue a hybrid model for the cartridges that retained the individual cartridges but held them together with a proprietary 3D printed cap/holder. This solution, which enabled us to mimic a single cartridge, allowed us to quickly fabricate prototype single cartridges suitable for testing in a PoC study, thereby avoiding costly bespoke, injection molding and was deemed to be a suitable solution whilst still in the prototype stage.
With the new single cartridge prototype in hand, we entered into a collaboration with engineering students at ETH-Zürich, which produced a design prototype that incorporated the single cartridges and a design for a cartridge closing/locking mechanism. Alongside this design project, a new functional prototype was optimized, sourced and assembled, which included a new mechanism for closing and locking the single cartridges in place.
In addition to the cartridge and machine design optimization, a postdoc, funded by this ERC PoC project, optimized the synthetic routes to twelve solid-supported N-heterocycle forming reagents, which were then outsourced for a larger scale synthesis to a CRO partner in India. Using the material provided by the CRO the postdoc was able to fully define the scope of the machine capabilities using a wide panel of aldehydes.
Furthermore, investigations into expansion of the machine concept were supported by this ERC PoC grant, including the design and assembly of a prototype photoreactor. These findings will be incorporated into future generations of the machine or will be offered as additional add-on products to expand the market.
Ultimately, with the machine and single cartridge prototypes in hand, along with the fully defined scope, all the steps critical for commercialization were achieved. As a result a Spinoff company – Synple Chem AG – was able to raise funds (1m CHF ) in a series A investment round, which has financed the development and assembly of ten beta-versions of the machine for beta-testing with customers from drug-discovery organizations. With this first milestone successfully achieved, further funds are expected to be released imminently to finance the beta-test phase. However, even ahead of this, income is already being generated from the sales of cartridges to beta-testers (a discounted price of CHF 105-130 was offered to beta-testers) and this is being utilized to ensure a steady supply of reagent cartridges for the entire beta-test phase. Upon completion of the beta-test phase, further investment will be sought to ensure that feedback can be implemented ahead of a full market launch.
Upon market launch, we expect the machine, which provides a safe, rapid, one-button approach to N-heterocycles, to fit well with the growing needs in our target market: the reduction of researchers’ exposure to toxic materials, automation, the acceleration of organic synthesis, and the preparation of more “drug-like” molecules at earlier stages of research and development. We expect it have a high impact by helping to accelerate the drug discovery process. Furthermore, we anticipate that the underlying concepts – cartridge-based reagents that deliver exactly the amount needed for a successful organic transformation – can be readily extended to many different reaction classes. In the future, we envision that small, self-contained, cartridge-based machines will emerge as the method of choice for a significant proportion of routine organic transformation and, as such, much of the development work that is currently outsourced to non-EU countries will be safely and willingly conducted in EU research labs.
Prior to the start of this project we had developed a flow-based prototype for the preparation of saturated N-heterocycles – an important structural class in drug discovery, which we nicknamed the “Hetspresso Machine”. Our key advance was the technology to immobilize heterocycle-forming reagents, based on the “SnAP reagents” that were developed in the course of an ERC StG. This new, immobilized reagent approach enabled the fabrication of disposable cartridges that delivered exactly the right amount of SnAP reagent for full conversion of an aldehyde substrate to the desired N-heterocycle. In addition, by using the flow-based prototype and disposable cartridges, all steps of the process could be carried out in a far safer manner since they occur in either the machine or the disposable cartridges. Productivity also had the potential to be enhanced because the fully automated process required no workup or purification, and took only a fraction of the “hands-on” time compared to the original SnAP process.
Although, prior to the initiation of this project, a few different “flavors” of SnAP cartridges had been tested, more studies and refinements to improve the scope were required. In addition, in order to simply the process for the user redesign of the cartridge was also required so that the four individual reagent cartridges used with the initial prototype could be integrated into a single cartridge. In order to incorporate the new cartridge design, some machine engineering optimization would also be required. ERC PoC funding was obtained to support these crucial developments and help achieve the ultimate goal of enabling a user to simply insert one of a range of different “flavors” of SnAP cartridge into the machine, and upon addition of the starting material, press a single button to start the whole automated process.
A portion of the ERC PoC funding was earmarked for the development and optimization of a single, disposable reagent cartridge system for use in the automated machine. A second part of the funding was allocated for the machine engineering optimization and construction of a fully operational, cartridge-based machine, which would serve as a demonstration model. A further portion of the funding was to be used to prepare a range of different “flavours” of N-heterocycle cartridges, which would allow us to fully determine the scope of the “Hetspresso Machine”. Finally, the remainder of the funding was assigned to support expansion of the concept to other reaction classes. Achievement of these four goals was crucial for the commercialization of this technology.
From the outset of the project, the aim was to redesign the cartridge and holder so that the four independent reagent cartridges that held the required immobilized reagents for the N-heterocycle forming process could be incorporated into a single, proprietary cartridge that could readily be loaded into the machine by a pressure-locking system or similar design. Based on customer feedback, we opted to pursue a hybrid model for the cartridges that retained the individual cartridges but held them together with a proprietary 3D printed cap/holder. This solution, which enabled us to mimic a single cartridge, allowed us to quickly fabricate prototype single cartridges suitable for testing in a PoC study, thereby avoiding costly bespoke, injection molding and was deemed to be a suitable solution whilst still in the prototype stage.
With the new single cartridge prototype in hand, we entered into a collaboration with engineering students at ETH-Zürich, which produced a design prototype that incorporated the single cartridges and a design for a cartridge closing/locking mechanism. Alongside this design project, a new functional prototype was optimized, sourced and assembled, which included a new mechanism for closing and locking the single cartridges in place.
In addition to the cartridge and machine design optimization, a postdoc, funded by this ERC PoC project, optimized the synthetic routes to twelve solid-supported N-heterocycle forming reagents, which were then outsourced for a larger scale synthesis to a CRO partner in India. Using the material provided by the CRO the postdoc was able to fully define the scope of the machine capabilities using a wide panel of aldehydes.
Furthermore, investigations into expansion of the machine concept were supported by this ERC PoC grant, including the design and assembly of a prototype photoreactor. These findings will be incorporated into future generations of the machine or will be offered as additional add-on products to expand the market.
Ultimately, with the machine and single cartridge prototypes in hand, along with the fully defined scope, all the steps critical for commercialization were achieved. As a result a Spinoff company – Synple Chem AG – was able to raise funds (1m CHF ) in a series A investment round, which has financed the development and assembly of ten beta-versions of the machine for beta-testing with customers from drug-discovery organizations. With this first milestone successfully achieved, further funds are expected to be released imminently to finance the beta-test phase. However, even ahead of this, income is already being generated from the sales of cartridges to beta-testers (a discounted price of CHF 105-130 was offered to beta-testers) and this is being utilized to ensure a steady supply of reagent cartridges for the entire beta-test phase. Upon completion of the beta-test phase, further investment will be sought to ensure that feedback can be implemented ahead of a full market launch.
Upon market launch, we expect the machine, which provides a safe, rapid, one-button approach to N-heterocycles, to fit well with the growing needs in our target market: the reduction of researchers’ exposure to toxic materials, automation, the acceleration of organic synthesis, and the preparation of more “drug-like” molecules at earlier stages of research and development. We expect it have a high impact by helping to accelerate the drug discovery process. Furthermore, we anticipate that the underlying concepts – cartridge-based reagents that deliver exactly the amount needed for a successful organic transformation – can be readily extended to many different reaction classes. In the future, we envision that small, self-contained, cartridge-based machines will emerge as the method of choice for a significant proportion of routine organic transformation and, as such, much of the development work that is currently outsourced to non-EU countries will be safely and willingly conducted in EU research labs.