Cancer Research - Europa

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