| Doctorant : |
Lucie FONTENEAU
|
| Directeur de thèse : |
Fabrice FLEURY ,
Professeur Université |
| co-directeur de thèse : | CHESNAIS Benoît |
| Financement : |
Nantes Université et Le Mans Université |
| Date de la soutenance : |
vendredi 31 mai 2024, 14h00 |
| Modalité : |
- Lieu : Amphithéâtre D, bâtiment 1, campus Lombarderie
|
| Jury : |
- Rapporteur : Mauro MODESTI, DR, CRCM, Université Aix-Marseille
- Rapporteur : Vincent PARISSI, DR, LMFP, Université de Bordeaux
- Examinateur : Ibtissam TALHAOUI, CR, CBM, Orléans
- Examinateur : Monique MATHE, CR CEISAM, Nantes Université
- Directeur de thèse :
Fabrice FLEURY ,
Professeur Université
- co-directeur de thèse : CHESNAIS Benoît
|
Les cassures double brin de l’ADN sont les plus délétères pour une cellule. L’une des voies de réparation de ces dommages est la recombinaison homologue (RH) impliquant la protéine RAD51. Cette recombinase joue un rôle central dans la RH et est surexprimée dans les cellules cancéreuses. La réparation accrue des dommages à l’ADN par les cellules tumorales conduit le plus souvent au développement de résistances aux thérapies anticancéreuses, limitant leur efficacité. RAD51 a déjà fait l’objet de ciblage par différentes approches. Son inhibition a notamment permis de sensibiliser les cellules cancéreuses aux traitements. Nous avons ici pu mettre en évidence des petites molécules capables de moduler l’activité de RAD51 in vitro et également de sensibiliser des cellules cancéreuses en association avec le cisplatine.
Publications
2023
Demeyer, Alexandre; Fonteneau, Lucie; Liennard, Marion; Foyer, Claire; Weigel, Pierre; Laurent, Adèle; Lebreton, Jacques; Fleury, Fabrice; Mathé-Allainmat, Monique
Synthesis and Biological Evaluation of DIDS Analogues as Efficient Inhibitors of RAD51 Involved in Homologous Recombination Article de journal
Dans: Bioorg Med Chem Lett, p. 129261, 2023, ISSN: 1464-3405.
@article{pmid36990245,
title = {Synthesis and Biological Evaluation of DIDS Analogues as Efficient Inhibitors of RAD51 Involved in Homologous Recombination},
author = {Alexandre Demeyer and Lucie Fonteneau and Marion Liennard and Claire Foyer and Pierre Weigel and Adèle Laurent and Jacques Lebreton and Fabrice Fleury and Monique Mathé-Allainmat},
url = {hal-04234850v1 },
doi = {10.1016/j.bmcl.2023.129261},
issn = {1464-3405},
year = {2023},
date = {2023-03-01},
urldate = {2023-03-01},
journal = {Bioorg Med Chem Lett},
pages = {129261},
abstract = {RAD51 is a pivotal protein of the homologous recombination DNA repair pathway, and is overexpressed in some cancer cells, disrupting then the efficiency of cancer-treatments. The development of RAD51 inhibitors appears as a promising solution to restore these cancer cells sensitization to radio- or chemotherapy. From a small molecule identified as a modulator of RAD51, the 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), two series of analogues with small or bulky substituents on the aromatic parts of the stilbene moiety were prepared for a structure-activity relationship study. Three compounds, the cyano analogue (12), and benzamide (23) or phenylcarbamate (29) analogues of DIDS were characterized as novel potent RAD51 inhibitors with HR inhibition in the micromolar range.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
RAD51 is a pivotal protein of the homologous recombination DNA repair pathway, and is overexpressed in some cancer cells, disrupting then the efficiency of cancer-treatments. The development of RAD51 inhibitors appears as a promising solution to restore these cancer cells sensitization to radio- or chemotherapy. From a small molecule identified as a modulator of RAD51, the 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), two series of analogues with small or bulky substituents on the aromatic parts of the stilbene moiety were prepared for a structure-activity relationship study. Three compounds, the cyano analogue (12), and benzamide (23) or phenylcarbamate (29) analogues of DIDS were characterized as novel potent RAD51 inhibitors with HR inhibition in the micromolar range.