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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

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-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).
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https://hal.archives-ouvertes.fr/hal-03414007
Contributor : Laurent Jonchère Connect in order to contact the contributor
Submitted on : Monday, November 22, 2021 - 2:56:29 PM
Last modification on : Friday, May 13, 2022 - 3:48:52 PM
Long-term archiving on: : Wednesday, February 23, 2022 - 7:39:46 PM

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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 and Biomolecular Chemistry, Royal Society of Chemistry, 2021, 19 (41), pp.8968-8987. ⟨10.1039/d1ob01521d⟩. ⟨hal-03414007⟩

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