IMED Biotech Unit
Collaboration Update
X-Chem and AstraZeneca:
Innovative technology partnership to
identify lead molecules for
drug discovery
“
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.
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 proteinprotein 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.
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.
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.
What’s special about the collaboration?
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
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 proteinprotein 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.”