XPF-ERCC1

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

 Coordinatore  

 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

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

ercc    cancer    chemotherapeutic    pharmacological    kinetic    structure    platinum    structural    damage    treatment    dna    drug    pathways    resistance    xpf    agents    cell    induced    repair    inhibitors    function   

 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.'

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