Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues

Hippolyte Paysant (1, 2) , Siham Hedir (1, 2) , Frédéric Justaud (3) , Louis Bastien Weiswald (1, 2) , Assaad Nasr El Dine (3, 4) , Ali Soulieman (3, 4) , Ali Hachem (4) , Nicolas Elie (5) , Emilie Brotin (1, 5, 6, 2) , Christophe Denoyelle (1, 5, 6, 2) , Jérome Bignon (7) , Fanny Roussi (7) , Marie Jouanne (8) , Olivier Tasseau (3) , Thierry Roisnel (3) , Anne Sophie Voisin-Chiret (8) , Rene Gree (3) , Nicolas Levoin (9) , Laurent Poulain (1, 2)

1 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
2 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
3 ISCR - Institut des Sciences Chimiques de Rennes
4 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
5 ICORE - Interactions Cellules Organismes Environnement
6 ImpedanCELL
7 ICSN - Institut de Chimie des Substances Naturelles
8 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
9 Bioprojet-Biotech

In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-x(L)/Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure-activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-x(L).

Domaines: Chimie thérapeutique; Cancer

Hippolyte Paysant, Siham Hedir, Frédéric Justaud, Louis Bastien Weiswald, Assaad Nasr El Dine, et al.. Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues. Organic & Biomolecular Chemistry, 2021, 19 (41), pp.8968-8987. ⟨10.1039/d1ob01521d⟩. ⟨hal-03414007⟩