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

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.