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DEPPICT<br />
Designing Therapeutic Protein-Protein<br />
Inhibitors for Brain <strong>Cancer</strong> Treatments<br />
Summary<br />
Keywords | Protein-Protein interactions | small molecule inhibitors | knowledge driven drug design |<br />
blood/brain | tumour penetrant |<br />
Protein-Protein interactions (PPI) are central elements in<br />
cellular processes and important targets for selective therapeutic<br />
agents. They constitute a rich area for discovery<br />
of novel small ligand-based therapies. This proposal seeks<br />
to utilise such interactions, in particular those featuring<br />
a a-helix binding groove such as p53-MDM2, or more novel<br />
targets, e.g. nm23-prune, to develop targeted small-molecule<br />
libraries with physico-chemical properties appropriate<br />
for therapeutic eff ect against various tumour types such as<br />
the brain cancers of glioblastoma and medulloblastoma.<br />
Combination of the concepts below should provide an<br />
opportunity to unlock the potential of protein interactions<br />
as key components in signalling pathways via design of<br />
selective small-molecule modulators targeting the kinaseeff<br />
ector interaction instead of the ATP active site.<br />
• Develop an understanding of the elements controlling<br />
selectivity in Protein-Protein signalling networks by<br />
developing approaches for design of small molecules<br />
that target a-helix binding groove interactions through<br />
use of structure-based and fragment-based approaches.<br />
• Data-mining of ADME and drug-drug interactions to<br />
build a predictive database for library design.<br />
• Develop quantitative structure/property relationships,<br />
with an emphasis on CYP-mediated metabolism, ABC<br />
transporters at the blood/brain and brain/tumour<br />
interfaces, mutagenicity, solubility, pKa, and passive<br />
permeability, and predictive tools for mutagenicity and<br />
other genetic toxicology end-points.<br />
• Develop predictive PK and PBPK models to improve<br />
understanding of BBB and tumour penetration.<br />
• In vitro and in vivo PK/PD and TK/TD characterisation<br />
of compounds, to increase understanding of their mechanism<br />
of action and reduce the use of laboratory<br />
animals.<br />
Such knowledge-based approaches will also be applicable<br />
to design of small molecules for other Protein-Protein interactions<br />
utilising a a-helix binding groove both for peripheral<br />
tumours and other therapeutic areas.<br />
Problem<br />
Amongst the range of cancer types, brain and perhaps pancreatic<br />
cancers are especially lacking in eff ective treatments.<br />
In particular brain tumours are:<br />
• the leading cause of death from childhood cancers<br />
among persons under 19;<br />
• the second leading cause of cancer-related deaths in<br />
males aged 20-39;<br />
• the fi fth leading cause of cancer-related deaths in women<br />
aged 20-39.<br />
Although onset of disease varies with tumour type, it can<br />
occur at a relatively young age causing additional and signifi<br />
cant social and economic problems for both patients and<br />
their families.<br />
Current standard treatments include surgery, radiation therapy<br />
and chemotherapy. These may be used either individually<br />
or typically in combination. Brain cancers however present<br />
unique problems due to the location of the tumours: surgery<br />
and radiotherapy carry considerable risk to the patient and<br />
resection is not always possible. Chemotherapy is faced with<br />
the problem of penetration of drugs across the blood-brain<br />
barrier (BBB) and of lack of specifi city. The focus for these<br />
patients is therefore on more eff ective therapies to prevent<br />
relapse, and on more effi cient screening and diagnosis to<br />
halt the disease at an early stage.<br />
Aim<br />
The main objective of the proposed project is to provide<br />
more eff ective anti-tumour therapies by developing targeted<br />
small ligand libraries with appropriate physico-chemical<br />
properties for therapeutic eff ect targeted against Protein-<br />
Protein interactions implicated in various tumour types. The<br />
research activities will concentrate on knowledge-based<br />
approaches supporting translational research aimed at<br />
bringing basic knowledge through to applications in clinical<br />
practice and public health. The project will thus focus on<br />
providing small molecule ligands with minimal side eff ects<br />
as treatments for the brain tumours glioblastoma (GBM)<br />
and medulloblastoma.<br />
Expected results<br />
The successful integration of the various aspects of this proposal<br />
will provide a robust knowledge-based strategy for<br />
exploiting Protein-Protein interactions as drug targets in the<br />
treatment of brain tumours. The strategy should however be<br />
suffi ciently generic to be transferable to other disease areas,<br />
especially within the CNS, where Protein-Protein interactions<br />
provide an entry point into disease-modifying therapies.<br />
188 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME