D’une part, dans le cadre de l’axe PPI RhoA, il consiste à développer des petites molécules en tant qu’inhibiteurs spécifiques de l’interaction GEF/GTPase de Rho. Leur conception rationnelle s’appuiera sur les informations mécanistiques et structurales de cette interaction grâce à un large éventail de méthodes de simulation par modélisation moléculaire, ce qui permettra d’améliorer la compréhension du (ou des) site(s) RhoGEF essentiels à l’activation de ces GTPases. Cette stratégie sera d’abord appliquée au couple Arhgef1/RhoA que nous avons récemment identifié comme cible pertinente pour le développement de nouveaux traitements contre l’hypertension et l’athérosclérose.http://piramid-research.fr/ppi-rhoa/
D’autre part, dans le cadre de l’axe PPI Rad51, il consiste à développer de nouveaux inhibiteurs de Rad51 spécifiques des interfaces protéiques autour d’une molécule matrice découverte par une équipe japonaise, le DIDS (4,4′-Diisothiocyano-2,2′-stilbene disulfonic acid). Ces travaux pourraient permettre d’ouvrir de nouvelles perspectives en terme de développement d’agents sensibilisateurs aux thérapies anticancéreuses mais également en terme de compréhension du mécanisme de réparation de l’ADN par recombinaison homologue.http://piramid-research.fr/ppi-rad51/
@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.
@article{velic_molecular_2021,
title = {Molecular Determinant of DIDS Analogs Targeting RAD51 Activity},
author = {Denis Velic and Alexandre Demeyer and Thibaut Peterlini and Houda Benhelli-Mokrani and Monique Mathé-Allainmat and Jean-Yves Masson and Fabrice Fleury},
url = {https://www.mdpi.com/1420-3049/26/18/5460},
doi = {10.3390/molecules26185460},
issn = {1420-3049},
year = {2021},
date = {2021-09-15},
urldate = {2021-09-15},
journal = {Molecules},
volume = {26},
number = {18},
pages = {5460},
abstract = {RAD51 is the central protein in DNA repair by homologous recombination (HR), involved in several steps of this process. It is shown that overexpression of the RAD51 protein is correlated with increased survival of cancer cells to cancer treatments. For the past decade, RAD51 overexpression-mediated resistance has justified the development of targeted inhibitors. One of the first molecules described to inhibit RAD51 was the 4,4 -diisothiocyanato-stilbene-2,2 -disulfonic acid (DIDS) molecule. This small molecule is effective in inhibiting different functions of RAD51, however its mode of action and the chemical functions involved in this inhibition have not been identified. In this work, we used several commercial molecules derived from DIDS to characterize the structural determinants involved in modulating the activity of RAD51. By combining biochemical and biophysical approaches, we have shown that DIDS and two analogs were able to inhibit the binding of RAD51 to ssDNA and prevent the formation of D-loop by RAD51. Both isothiocyanate substituents of DIDS appear to be essential in the inhibition of RAD51. These results open the way to the synthesis of new molecules derived from DIDS that should be greater modulators of RAD51 and more efficient for HR inhibition.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
RAD51 is the central protein in DNA repair by homologous recombination (HR), involved in several steps of this process. It is shown that overexpression of the RAD51 protein is correlated with increased survival of cancer cells to cancer treatments. For the past decade, RAD51 overexpression-mediated resistance has justified the development of targeted inhibitors. One of the first molecules described to inhibit RAD51 was the 4,4 -diisothiocyanato-stilbene-2,2 -disulfonic acid (DIDS) molecule. This small molecule is effective in inhibiting different functions of RAD51, however its mode of action and the chemical functions involved in this inhibition have not been identified. In this work, we used several commercial molecules derived from DIDS to characterize the structural determinants involved in modulating the activity of RAD51. By combining biochemical and biophysical approaches, we have shown that DIDS and two analogs were able to inhibit the binding of RAD51 to ssDNA and prevent the formation of D-loop by RAD51. Both isothiocyanate substituents of DIDS appear to be essential in the inhibition of RAD51. These results open the way to the synthesis of new molecules derived from DIDS that should be greater modulators of RAD51 and more efficient for HR inhibition.
