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Designing therapeutic protein-protein inhibitors for brain cancer treatments

Project information

Grant agreement ID: 37834

  • Start date

    1 April 2007

  • End date

    30 September 2010

Funded under:

FP6-LIFESCIHEALTH

  • Overall budget:

    € 5 495 613

  • EU contribution

    € 3 640 293

Coordinated by:

SIENA BIOTECH SPA

Italy

Objective

Protein-protein interactions 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 an alpha-helix binding groove, such as p53-MDM2, or more novel targets e.g. n23-prune to develop targeted small molecule libraries with physico-chemical properties appropriate for therapeutic effect 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 kinase-effector interaction instead of the ATP active site.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 reduced the use of laboratory animals.Develop an understanding of the elements controlling selectivity in protein-protein signalling networks by developing approaches for design of small molecules that target alpha-helix binding groove interactions through use of structure based and fragment based approaches. Such knowledge-based approaches will also be applicable to the design of small molecules for other protein-protein interactions that utilize an alpha-helix binding groove and for other therapeutic areas.

Coordinator

SIENA BIOTECH SPA

Address

Banchi Di Sotto, 34
Siena

Italy

Participants (7)

MOLECULAR DISCOVERY

United Kingdom

CRYSTAX PHARMACEUTICALS S.L.

Spain

AUREUS-PHARMA S.A.

France

UNIVERSITY OF NEWCASTLE UPON TYNE

United Kingdom

THE CHNCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

United Kingdom

UNIVERSITA DEGLI STUDI DI PERUGIA

Italy

UNIVERSITA DEGLI STUDI DI SIENA

Italy

Project information

Grant agreement ID: 37834

  • Start date

    1 April 2007

  • End date

    30 September 2010

Funded under:

FP6-LIFESCIHEALTH

  • Overall budget:

    € 5 495 613

  • EU contribution

    € 3 640 293

Coordinated by:

SIENA BIOTECH SPA

Italy