Cancer Research - Europa

Keywords | Identifi cation of novel compounds | natural products | inhibition of protein-protein interactions |
high-throughput screening |
CAPPELLA
Combating cancer through novel
approaches to protein-protein
interaction inhibitor libraries
Summary
The inhibition of protein-protein interactions (PPI) is one of
the most promising approaches to the development of novel
cancer therapies. This project brings together some of
Europe’s leading biotech SMEs and several highly recognised
academic institutes. By combining fi ve distinct chemical
approaches and testing them on three diff erent targets (all
from diff erent partners) a series of innovative small-ligand
tools and libraries that allow new approaches to the inhibition
of PPI in cancer will be developed. The project is a unique
opportunity to integrate novel in silico, chemical, genetic
and ADME-based approaches to the design, synthesis and
optimisation of libraries and compounds.
Problem
Most protein-protein interactions occur within the cell and
thus can only be targeted by small molecules. Furthermore,
PPI diff er structurally from more classic drug targets such
as enzymes and receptors, and consequently existing
compounds have generally delivered disappointing results.
Therefore, new approaches are needed to develop novel
small molecules which inhibit PPI in cancer.
Aim
The objective of this project is to develop a series of innovative
smallligand tools and libraries that allow new approaches
to the inhibition of protein-protein interactions in cancer. A key
theme is the utilisation of structural motifs found in natural
PPI-inhibitor compounds. This is coupled with high content
testing of the resultant structures on three distinct PPI targets
relevant to diff erent types of cancer, to allow compound rulesets
to be developed and improved. We want to develop
small-ligand libraries focused on PPI inhibitors of relevance to
cancer. Furthermore, we will develop innovative tools that
allow improved library design in this area by integrating in silico
approaches, bio-informatics, new approaches to compound
synthesis and pharmacology. The project will also cover the
scientifi c areas such as in silico prediction of drug-like properties,
prediction of ADME parameters, predictive toxicology
and creation of virtual libraries.
Expected results
Innovative tools for designing PPI inhibitors
• Five diff erent PPI-inhibitor library creation tools, based
on fi ve complementary approaches:
• in silico;
• genetic chemistry;
• advanced natural product technologies;
• retro-synthesis of natural scaff olds;
• ADME improvement.
• Cross-fertilisation of approaches so that each of the fi ve
approaches learns lessons from the others and incorporates
relevant leanings into its approach.
• Three high-content assay systems for three important
PPI cancer targets (p53-Mdm2, Beta catenin-TCF4,
BRCA2-RAD51).
• Design rules for PPI inhibitor compound libraries (mass,
diversity composition, lipophilicity, compound class etc.)
generated from 15 complementary data sets.
Novel small-ligand libraries and pre-clinical candidates
• Several ‘PPI inhibitor’ compound libraries.
• Diff erent candidate compound families from within these
libraries that can subsequently be taken forward into
pre-clinical testing by the SME partners.
Libraries containing extracts of biological material off er great chemical diversity.
BIOLOGY 19