SCIENTIFIC REPORT 2015

Group Leader
Donald Ogilvie
Head of Chemistry
Allan Jordan
Head of Bioscience
Ian Waddell
Chemists
Jonathan Ahmet¹
Roger Butlin
Niall Hamilton
James Hitchin
Colin Hutton²
Stuart Jones
Chris Kershaw¹
Alison McGonagle
Rebecca Newton
Ali Raoof
Kate Smith
Bohdan Waszkowycz
Bioscientists
Ben Acton
Mentxu Aiertza Otxoterna¹
Habiba Begum¹
Elizabeth Blaikley¹
Charlotte Burt¹
Phil Chapman
Mark Cockerill
Emma Fairweather
Samantha Fritzl
Louise Griffiths¹
Nicola Hamilton
Sarah Holt²
Gemma Hopkins
Dominic James
Paul Kelly¹
Nikki March
Helen Small
Alex Stowell
Graeme Thomson
Adnana Tudose¹
Graeme Walker¹
Mandy Watson
DRUG DISCOVERY
www.cruk.manchester.ac.uk/Research/CRUK-MI-Groups/
Drug-Discovery/Home
The past 12 months have seen significant changes in the
Drug Discovery Unit as we strengthen both our team and
infrastructure to position ourselves for future success. This
has involved an increase in the size of the group by around
20% and the use of new technologies.
In particular, the establishment of a dedicated
target validation team will help ensure a steady
flow of new, clinically relevant, drug targets
for the group to prosecute. We have also
strengthened our informatics capabilities to
help our project decision-making and seen
delivery of considerable success in X-ray
crystallography, which will directly influence
our chemistry strategy over the coming months.
Progressing our project portfolio
During 2015, five of the projects in our drug
discovery portfolio underwent phase
transitions to more advanced stages.
After an extensive medicinal chemistry
campaign in the PARG project, we have
identified a structurally diverse shortlist of
compounds with pharmacokinetic properties
suitable for pharmacodynamic assessment and
these studies are presently underway. We
disclosed the underlying pharmacology of
these first-in-class compounds for the first time
in an oral presentation at the 2015 AACR annual
meeting in Philadelphia and have recently
completed filings of two chemical patent
applications for our lead series in PARG; these
will be published in May 2016. This planned
structural disclosure has provided us with
opportunities to share our proprietary in vitro
tool compounds with several key collaborators
so that we can expand, and subsequently
publish, additional mechanistic understanding
around this important DNA repair drug
discovery target.
The RET project has benefited greatly from
top-up funding from Sixth Element Capital
which was used to access additional chemistry,
crystallography, pharmacology and drug
metabolism resources. This has allowed the
identification of potent, selective RET inhibitors
with pharmacokinetic properties suitable for
investigation of efficacy. Intriguingly, high
resolution co-crystals with compounds from
this series reveal a hitherto unprecedented
binding mode to the RET protein, and provides
a clear rationale for their exquisite selectivity.
We have also made significant progress on
the targeting of anticipated RET inhibitor
resistance mutants. Using a combination of
computational modelling and virtual screening
we have identified novel potent and mutant
RET-selective hit matter with submicromolar
activity in cells. Representatives of four distinct
series have also been successfully characterised
at high resolution in co-crystals by our
collaborator, Dr Richard Bayliss at the University
of Leicester. These data reveal the precise
binding mode of inhibitors to the enzyme
protein and provide further medicinal
chemistry opportunities.
During the last year, our collaboration with the
GlaxoSmithKline (GSK) Cancer Epigenetics
Discovery Performance Unit based in
Philadelphia has progressed rapidly and in April,
the project transitioned into Lead Identification
phase. Since then, progress on the project
accelerated further and less than six months
later is now in the Lead Optimisation phase. One
of the attractions of the DDU for our external
partners is our proximity to expert scientists in
the Institute and we have provided early
proprietary epigenetic tool compounds from
this project to Dr Tim Somervaille’s team for
investigation of their preclinical pharmacology
in Acute Myeloid Leukaemia models. We have
continued to develop an excellent working
relationship with our partners in GSK and are
currently exploring the possibility of
collaboration on additional epigenetic targets.
Graduate Students
Elizabeth Hogg¹
Daniel Mould
Undergraduate Students
Kelly Ayton²
Shaun Johns¹
1
joined in 2015
2
left in 2015
Figure 1
The enhanced DDU team.
Figure 2
Crystal structure of a DDU
inhibitor (in green) bound to
mutant IDH1-1.
SMARCA2, our first target to have been
identified by bioinformatics, has now been fully
validated internally and has progressed into Hit
Identification. This target and our approach to it
attracted a lot of interest when we presented a
poster on it at the AACR annual meeting. This
resulted in discussions with several
Biotechnology and Pharma companies who
expressed an interest in collaborating with us on
this exciting target. We are currently progressing
the Pharma collaboration that gives us the most
potential to take this challenging project
forward.
Lastly, through a screening arrangement with
AstraZeneca, we successfully validated a
fascinating chemical series as inhibitors of the
oncometabolite enzyme mutant IDH1. This is a
target that has long been of interest to the team
but has so far proved challenging to find
credible hit matter. Collaboration with Dr Colin
Levy at The University of Manchester delivered
high-resolution crystal structures of these early
ligands bound to the target protein and these
provided inspiration for an aggressive medicinal
chemistry campaign. However, acceptable
pharmacokinetic properties proved difficult to
obtain and, given the significant competition,
the difficult decision to stop this project was
taken in order to allow us to focus upon our
more competitive and advanced projects.
With three resource-intensive, Lead
Optimisation projects progressing at the same
time, it has been difficult to invest as much effort
as we would like in new projects to refresh the
portfolio. This problem was recognised by
CRUK and from April 2015 we were awarded
additional ongoing funding to allow expansion
of our target identification and validation
capabilities. After an intensive recruitment
campaign we have appointed six new drug
discovery scientists and now have a “ring
fenced” target validation team, including our first
biology PhD student. We are particularly
focusing our efforts and reaching out to
potential collaborators around DNA Damage
Response/Synthetic Lethality, Epigenetic
Mechanisms and Lung Cancer as priority areas.
With our RET and PARG inhibitors, and working
with internal and external Principal Investigators,
we are also establishing an interest in additional
disease areas including Prostate and Pancreatic
Cancers. These efforts will bear fruit in 2016 and
the years to come. Closer to home, we
continue to engage with our local PIs to discuss
and progress novel drug discovery targets.
The Future
The primary aim of the DDU in this
quinquennium is to deliver our first candidate
drug into pre-clinical development through our
own efforts alone or in partnership with a
collaborator. During 2015, we have made
significant progress towards this objective and
have also taken steps to ensure the long term
sustainability of our project portfolio.
Publications listed on page 55
24 SCIENTIFIC REPORT 2015 CANCER RESEARCH UK MANCHESTER INSTITUTE DRUG DISCOVERY
25