Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode

Siham Hedir 1, 2 Marcella de Giorgi 3 Jade Fogha 3 Martina de Pascale 3 Louis-Bastien Weiswald 1, 2 Emilie Brotin 1, 2 Bogdan Marekha 3 Christophe Denoyelle 1, 2 Camille Denis 3 Peggy Suzanne 3 Fabien Gautier 4, 5 Philippe Juin 4, 5, * Laetitia Ligat 6 Frédéric Lopez 6 Ludovic Carlier 7 Rémi Legay 3 Ronan Bureau 3 Sylvain Rault 3 Laurent Poulain 1, 2, * Jana Sopkova-de Oliveira Santos 3, * Anne-Sophie Voisin-Chiret 3, *
* Corresponding author
1 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
2 ICM - UNICANCER - Institut régional du Cancer [Montpellier]
3 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
4 CRCINA - Département ONCO - Equipe 8 - Stress Adaptation and Tumor Escape in breast cancer - SATE
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
5 ICO Nantes - Institut de cancérologie de l'Ouest - Nantes
6 CRCT - Centre de Recherche en Cancérologie de Toulouse
7 LBM UMR 7203 - Laboratoire des biomolécules
Abstract : Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-x L and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl-2/Bcl-x L pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyr-idoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-x L targeting strategies.
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CNRS | VALDAURELLE | BACLESSE | ICO | GAUDUCHEAU | PAPIN | UNIV-ANGERS | FNCLCC | PSL | COMUE-NORMANDIE | CRCINA | UNIV-NANTES | UNICAEN | ENS-PARIS | U1086 | CERMN | SORBONNE-UNIVERSITE | ESPCI | ENSCP | INC-CNRS | PARISTECH | LBM | UNIV-TLSE3 | SU-SCIENCES

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Siham Hedir, Marcella de Giorgi, Jade Fogha, Martina de Pascale, Louis-Bastien Weiswald, et al.. Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode. European Journal of Medicinal Chemistry, Elsevier, 2018, 159, pp.357-380. ⟨10.1016/j.ejmech.2018.10.003⟩. ⟨inserm-01980723⟩

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