Flow Technology Innovations Driving Drug Discovery Forward

Flow chemistry is playing an increasingly prominent role in drug discovery, enabling those in the field to streamline chemistry discovery and development efforts. Finding ways to reduce the time it takes to generate validated small-molecule compounds would be highly advantageous – which is exactly why scientists at AbbVie developed SWIFT.

SWIFT (synthesis with integrated flow technology) is comprised of a flow reactor with a mass-triggered preparative HPLC/MS purification system. SWIFT enables the continuous synthesis of small-molecule libraries and is followed by immediate purification of each reaction – reducing the process time from 10 days to under 3 days.

We spoke with Dr Stevan Djuric, Vice President, Discovery Chemistry and Technology, AbbVie, to learn how this technology is impacting drug discovery. Stevan also discusses the team’s more recent efforts to develop a fully integrated and automated drug discovery platform.

Laura Mason (LM): Could you tell us more about SWIFT (synthesis with integrated flow technology)?

Stevan Djuric (SD): At AbbVie, we are always looking for places to invest in groundbreaking science to better help us solve important medical challenges. In the case of SWIFT, we were looking for ways to reduce cycle time for compound synthesis and purification as our previous process took around 10 days. With the adaptation of SWIFT, we were able to reduce that process down to between two and three days.

We became interested in segmented flow approaches to compound library synthesis coupled to in-line purification using LC-MS techniques. We considered a number of different options and eventually settled on an Accendo Conjure system which our in-house Automation Engineering group helped us couple to an LC-MS system for integrated purification and robotic weighing and labeling of library products.

We also added a proprietary sonication to prevent clogging of the reaction coil during synthesis. Reaction optimization could be aided by Design of Experiment (DoE) software provided with the Conjure.

This technology will be instrumental in streamlining our chemistry discovery and development efforts at AbbVie.

LM: What advantages does SWIFT have over other flow techniques?

SD: For library production, segmented flow is very useful because it allows for library members to be produced in a sequence of reaction segments separated by an inert solvent spacer. Essentially, SWIFT allows two processes to occur simultaneously – when one segment is being purified, others are in the flow coil reacting.

Previously, we used mass detection technology and only collected segments where we knew that the reaction had worked and this sped up the process. The integration of purification with the synthesis was our biggest challenge and took some technical innovation on the part of our AbbVie analytical chemistry team to solve.

LM: In 2014 you made alterations to the original SWIFT system, what changes were made and how did this affect the technology?

SD: The major changes were:

• the addition of enhanced robotics to allow for easier compound isolation after purification (solvent removal – V10 evaporator)
• analysis (e.g., NMR) and bar coding for submission to our compound repository
• implementation of proprietary sonication systems to prevent reaction clogging

LM: Could you give a specific example of a project that has utilized SWIFT?

SD: Recently, scientists at AbbVie used SWIFT to identify a clinical candidate for our Cystic Fibrosis CFTR corrector program.

We used our custom monomer/building block collection to iteratively produce libraries coupled with a handcrafted traditional medicinal chemistry approach to rapidly identify a clinical candidate in a highly accelerated timeline in a very competitive research area.

LM: More recently you have developed a fully integrated and automated drug discovery platform, could you tell us more about this platform and some of its benefits?

SD: The next logical step for us after developing the SWIFT platform was to see if we could achieve our long-term goal of developing a closed-loop system of synthesis-purification-bioassay.

After two-and-a-half years of development we rolled out our BioSip platform. This platform featured a versatile synthesis front end which could implement parallel synthesis via segmented flow, microwave or traditional vial in reaction block methodology (the latter using a ChemSpeed platform).

After synthesis, reaction products were filtered and purified, plated and stock solutions were made, and bioassays conducted using an Envision plate reader – all done with minimal human intervention. In this system, the major challenge proved to be an effective and accurate quantitation of library compounds after purification. Several analytical techniques were evaluated with CAD emerging as a winner.

BioSip reduced the synthesis-purification-bioassay cycle time from two weeks to three to four days and is now routinely used to support Hit to Lead programs. All of this innovative work, including implementation of the bioassays, was developed by AbbVie chemists.  In the future, we hope to expand the variety of assay formats available. 

Stevan Djuric was speaking to Laura Elizabeth Mason, Science Writer at Technology Networks.