Our vision from day one was to have a broad scope for working together. So if the initial collaboration was successful, our technology could be applied as one of AstraZeneca’s pillars of lead discovery on a permanent basis. Our aim is to have as many of our compounds as possible progressing to pre-clinical candidate stage. We are aiming to come up with molecules that we think will be drug candidates of the future. AstraZeneca leaders have given great guidance and support, which has been instrumental in making this collaboration work and is a huge part of our success.

Richard Wagner, President and CEO,X-Chem Inc.

IMED Biotech Unit

X-Chem and AstraZeneca:Innovative technology partnership toidentify lead molecules fordrug discovery

When we at AstraZeneca were looking for a new way to screen compounds to find molecular activity for target proteins, an emerging technology looked particularly interesting.

We wanted new ways of identifying lead molecules for important drug targets that would allow us to identify more molecules to take into lead optimization and to identify novel molecules for difficult ‘undruggable’ targets.To complement traditional high throughput screening, which typically assesses 2 million compounds per programme, we wanted a system that would enable us to screen billions of compounds to identify molecules for progression.

We approached X-Chem Inc., a U.S.-based biotechnology company and world experts in the discovery technology that interested us, establishing a collaboration that allowed us to ‘hit the ground running’ with this intense level of screening.

X-Chem uses its proprietary high-diversity library and ultra-efficient screening platform to improve the rate and quality of small molecule lead discovery and expand the realm of ‘druggable’ targets.

The DNA-encoded library is unmatched in size and diversity, with more than 100 billion molecules, growing in number each year. To work with such an enormous library, X-Chem has developed a robust platform including innovative screening methodologies based on affinity selection and a proprietary informatics and data analysis suite. This platform has been highly successful against historically challenging targets, including protein-protein interactions; epigenetic targets, the Ubiquitin family antibacterial targets and G-protein coupled receptors (GPCRs).

DNA encoded library technology allows us to create and screen hundreds of billions of small molecules linked to unique DNA barcodes. Libraries of compounds are screened by binding them to a protein target, with unbound molecules washed away. Enriched molecules bound to the target are identified via DNA sequencing and translation of the barcode back to chemical structures. Due to the large size of the libraries, molecules can be identified with unique properties not possible with other technologies.

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Collaboration Update

Collaboration in practice The pilot programme focussed on the identification of lead molecules for 20 targets. Within 12 months, we had sufficiently interesting data to justify an extension of the collaboration across multiple therapeutic areas.

The collaboration allows for 10 projects per year, so typically there are about 15 running at any one time. Each project has its own team, with X-Chem scientists paired up with our project teams.

A Joint Steering Committee sets the strategic course and meets quarterly to review progress. Ongoing interactions between scientific and alliance management leaders also ensure that the collaboration is strong and effective.

X-Chem perspective: “Today we’re looking at multiple therapeutic areas and have had numerous successes from our work together”, said Matt Clark, Senior VP of Research.

“We aim to publish a number of joint scientific articles over the next 12 months.”

“We have expanded our scope to work with AstraZeneca chemists to generate exclusive libraries of molecules using X-Chem technology and AstraZeneca chemical knowledge. Those dedicated libraries will be used to further expand the diversity of chemistry that can be probed using the platform.”

“It’s an open, highly collaborative relationship with several levels of interaction, including a recent visit by a large group of X-Chem scientists to several AstraZeneca sites. This has allowed for both sides to feel they are contributing intellectually. We’re pleased with how it’s going, and the high quality of science you get when two expert teams are working side-by-side in a focused way.”

Diala Ezzeddine, Executive VP and Chief Business Officer, X-Chem Inc, said: “These are difficult to drug targets. By enabling AstraZeneca to pursue these high value therapeutic targets, we are providing a unique capability to help build their pipeline. There is a groundswell of interest in this technology across the industry, and in our platform in

Early success from the collaboration with X-Chem led to AstraZeneca licensing drug discovery programmes covering oncology and respiratory/inflammation protein-protein interaction targets and several antibacterial targets.

Recent additional successes have included new programmes with a GPCR receptor involved in pain, a cardiovascular target, a number of kinase targets and further protein-protein interaction targets in the oncology space.

Our hope is that this will help identify candidate drugs, with activity at highly validated drug targets, which in turn will result in the generation of innovative new medicines for patients.

In addition, through the collaboration yet outside its original scope, we have a programme addressing a tuberculosis target. We will be submitting an application to the Wellcome Trust, to hopefully secure funding for an academic programme in a disease outside AstraZeneca’s core areas of focus.

particular. AstraZeneca recognised the innovation early on, they have been pioneers in effectively deploying the power of the platform to their advantage, which puts them ahead of many other pharma companies.”

AstraZeneca perspective: “Rather than screen millions of compounds, the DNA Encoded Library Technology allows us to screen billions – fast,” said Steve Rees, VP Screening Sciences & Sample Management.

“And that means we can quickly find a potential chemistry starting position. It complements our in-house methods. We expected to get more hits for targets we knew we could be successful with – and that’s exactly what’s happened. It also enabled us to tackle difficult targets, particularly protein-protein interactions and GPCRs and infection targets.But what surprised us is the number of hits we’re getting for areas where we hadn’t been successful before.

“Working with a partner who is focused on the technology enables us at AstraZeneca to keep up with innovations in this important field. It also aligns with our ambition to achieve scientific leadership and helps add value to our portfolio.”

What’s special about the collaboration?