The Institute of Cancer Research
Sections of Structural Biology and Cancer Therapeutics
PhD Studentship
Integration, application and development of biophysical techniques in
structure-based drug discovery
(Chelsea, London & Sutton, Surrey)
The Institute of Cancer Research is one of the world's leading cancer
research organisations and is internationally renowned for the
quality of its science. Our mission is the relief of human suffering
by pursuing excellence in the fight against cancer.
A Wellcome Trust funded PhD studentship is available from in Dr Rob
van Montfort’s Structure-Based Drug Design group from October 2008.
The PhD studentship involves the integration, application and
development of biophysical techniques such as isothermal titration
calorimetry (ITC), thermal shift analysis, and surface plasmon
resonance (SPR), into the fragment-based and structure-based drug
discovery strategy of The Institute.
In the last decade fragment-based lead discovery has become an
increasingly popular lead identification approach. In contrast to
conventional high-throughput screening (HTS), in which large compound
collections containing compounds with drug-like properties are
screened, fragment-based lead discovery is based on the screening of
libraries of molecules that are significantly smaller (Mr~ 120-250)
and functionally simpler. Simple fragments have a higher probability
of matching a given binding-site and the hit-rate in fragment-based
screening (FBS) is typically much higher than observed in HTS. In
addition, a well constructed fragment library samples chemical space
more efficiently than a traditional HTS library.
Although fragment hits are usually very efficient ligands, they
typically exhibit a much lower binding affinity (~100mM-mM) compared
to HTS hits and are therefore difficult to detect using traditional
bioassay-based screening methods. Biophysical techniques such as NMR
and X-ray crystallography are used in FBS, because they possess the
high sensitivity needed to detect low affinity fragments. However,
both methods have their limitations and therefore other biophysical
techniques such as surface plasmon resonance (SPR), thermal shift and
isothermal titration calorimetry (ITC) are often combined with
crystallography as they have the potential to rapidly identify and
characterise ligands of interest and obtain useful information about
the protein-ligand interactions involved.
This proposal offers the opportunity to apply several biophysical
techniques and crystallographic follow-up to key novel targets in The
Institute of Cancer Research portfolio to generate new, or additional
hit matter for prosecution in collaboration with in-house medicinal
chemistry teams. Examples of targets where we envisage applying
these techniques include the oncogenic molecular chaperone family and
checkpoint kinases as well as targets traditionally viewed as poorly
druggable (e.g. protein phosphatases) where new strategies for small
molecule hit discovery are an important medicinal chemistry challenge.
The position will be funded for 4 years by The Wellcome Trust. The
Year 1 tax-free stipend rates from 1 October 2008 will be £17,442
outside London (Sutton) and £19,508 in London (Chelsea). Informal
information about this PhD studentship can be made to Dr Rob van
Montfort [EMAIL PROTECTED] or Professor Julian Blagg
[EMAIL PROTECTED] For more information about The Institute of
Cancer Research please visit our website www.icr.ac.uk.
The aim of the Wellcome Trust PhD Programme in Mechanism-based Drug
Discovery is to train students who can work at the cutting edge of
one discipline as well as understand other biomedical areas well
enough to work as part of the interdisciplinary team necessary to
devise new therapies.
To apply please email your CV to [EMAIL PROTECTED]
Dr. Rob van Montfort
Team Leader Structure-Based Drug Design
Sections of Cancer Therapeutics and Structural Biology
The Institute of cancer Research
15 Cotswold Road
Sutton SM2 5NG
UK
Tel:
+44-(0)20-8722-4364 (Sutton)
+44-(0)20-7153-5142 (Chelsea)
Email: [EMAIL PROTECTED]
The Institute of Cancer Research: Royal Cancer Hospital, a charitable Company
Limited by Guarantee, Registered in England under Company No. 534147 with its
Registered Office at 123 Old Brompton Road, London SW7 3RP.
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