Structural and kinetic studies of XPF/ERCC1-DNA complex for drug discovery

Objectif

Cancer chemotherapeutic drugs, such as platinum agents, work by producing DNA damage that causes cell-cycle arrest and cell death. However, DNA repair pathways can enable tumour cells to survive DNA damage induced by chemotherapeutic treatments. Platinum resistance is a major clinical problem in cancer treatment and there is a considerable interest in inhibitors of DNA repair pathways, that can increase efficiency of chemotherapy, when administered together. An attractive target to circumvent platinum resistance is XPF/ERCC1 heterodimer. XPF/ERCC1 is a structure-specific endonuclease that cleaves double- to single-stranded DNA junctions, and its function is directly linked to repair of DNA cross-links induced by platinum agents. Here, we propose a multi-disciplinary methodology that combines structural studies by Nuclear Magnetic Resonance Spectroscopy with kinetic studies by Kinetic Capillary Electrophoresis to elucidate the mechanisms of XPF/ERCC1 function and modulate its activity for potential therapeutic benefit. Structural and molecular insights of DNA binding will be coupled with kinetic rates of DNA cleavage and enzyme/substrate interactions. The combined information will be used to develop XPF/ERCC1 inhibitors by in silico screening. Currently structure-kinetics relationship is not well explored in drug discovery, although the residence lifetime of a drug determines the duration of a pharmacological effect. The ability to combine structural and kinetic parameters in validating computational hits should identify compounds with desired pharmacological properties at early stages and facilitate faster optimization phase. The research proposed here is highly beneficial to public health, because it would allow to develop combination therapies for cancer treatment.

Champ scientifique

• sciences médicales et de la santé › médecine fondamentale › pharmacologie et pharmacie › découverte de médicaments
• sciences médicales et de la santé › sciences de la santé › santé publique et environnementale
• sciences naturelles › sciences biologiques › génétique › ADN
• sciences naturelles › sciences chimiques › chimie inorganique › métal de transition
• sciences médicales et de la santé › médecine clinique › oncologie

Programme(s)

• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Thème(s)

• FP7-PEOPLE-2013-IIF - Marie Curie Action: "International Incoming Fellowships"

Appel à propositions

FP7-PEOPLE-2013-IIF
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Régime de financement

MC-IIF - International Incoming Fellowships (IIF)

Coordinateur

Masarykova univerzita

Adresse

Zerotinovo Namesti 9
601 77 Brno
Tchéquie

Type d’activité

Higher or Secondary Education Establishments

Contact administratif

Veronika Papouskova (Dr.)

Liens

Contribution de l’UE

€ 146 005,20