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Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues†
Fr\u00e9d\u00e9ric Justaud,Ali Hachem,Nicolas Elie,J\u00e9r\u00f4me Bignon,Fanny Roussi,Marie Jouanne,Olivier Tasseau,Thierry Roisnel,Anne Sophie Voisin-Chiret,Ren\u00e9 Gr\u00e9e,Nicolas Levoin
Organic & Biomolecular Chemistry Pub Date : 2021/9/16 0:00:00 , DOI:10.1039/D1OB01521D
Abstract

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.

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