XPF-ERCC1

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

Coordinatore	more  Organization address address: Zerotinovo namesti 9 city: BRNO STRED postcode: 60177 contact info Titolo: Dr. Nome: Veronika Cognome: Papouskova Email: send email Telefono: +420 549494615
Nazionalità Coordinatore	Non specificata
Totale costo	146˙005 €
EC contributo	146˙005 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-I
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-10-01   -   2016-09-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	Masarykova univerzita  Organization address address: Zerotinovo namesti 9 city: BRNO STRED postcode: 60177 contact info Titolo: Dr. Nome: Veronika Cognome: Papouskova Email: send email Telefono: +420 549494615	CZ (BRNO STRED)	coordinator	146˙005.20

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 Obiettivo del progetto (Objective)

'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.'