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 Oct 27

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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-xL/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-xL.

Citation

Hippolyte Paysant, Siham Hedir, Frédéric Justaud, Louis Bastien Weiswald, Assaad Nasr El Dine, Ali Soulieman, Ali Hachem, Nicolas Elie, Emilie Brotin, Christophe Denoyelle, Jérôme Bignon, Fanny Roussi, Marie Jouanne, Olivier Tasseau, Thierry Roisnel, Anne Sophie Voisin-Chiret, René Grée, Nicolas Levoin, Laurent Poulain. 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 Oct 27;19(41):8968-8987