1. Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues.
- Author
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Paysant H, Hedir S, Justaud F, Weiswald LB, El Dine AN, Soulieman A, Hachem A, Elie N, Brotin E, Denoyelle C, Bignon J, Roussi F, Jouanne M, Tasseau O, Roisnel T, Voisin-Chiret AS, Grée R, Levoin N, and Poulain L
- Subjects
- Humans, Structure-Activity Relationship, Female, Cell Line, Tumor, Molecular Structure, Models, Molecular, Drug Screening Assays, Antitumor, bcl-X Protein antagonists & inhibitors, bcl-X Protein metabolism, Dose-Response Relationship, Drug, Apoptosis drug effects, Cell Proliferation drug effects, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Drug Design, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Ovarian Neoplasms metabolism
- 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-xL .- Published
- 2021
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