1. Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL‐1
- Author
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Aude Robert, Joëlle Wiels, Line Séguy, Fanny Roussi, Aurélie Malzert-Fréon, Cécile Apel, Sandy Desrat, Vincent Dumontet, Vincent Guérineau, Jérôme Bignon, Florian Daressy, Marc Litaudon, Anne-Claire Groo, Florian Malard, Ewen Lescop, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)
- Subjects
Cell Survival ,Stereochemistry ,Antineoplastic Agents ,Apoptosis ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,01 natural sciences ,Biochemistry ,Adduct ,Protein–protein interaction ,Structure-Activity Relationship ,chemistry.chemical_compound ,Protein Domains ,Cell Line, Tumor ,Drug Discovery ,Humans ,Cytotoxic T cell ,General Pharmacology, Toxicology and Pharmaceutics ,Mode of action ,Cell Proliferation ,bcl-2-Associated X Protein ,Pyrrole ,Polycyclic Sesquiterpenes ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Nuclear magnetic resonance spectroscopy ,0104 chemical sciences ,3. Good health ,010404 medicinal & biomolecular chemistry ,Cell culture ,Covalent bond ,Myeloid Cell Leukemia Sequence 1 Protein ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
International audience; Drimane sesquiterpenoid dialdehydes are natural compounds with antiproliferative properties. Nevertheless, their mode of action has not yet been discovered. In this publication, we have demonstrated that various drimanes are potent inhibitors of MCL-1 and BCL-xL, two proteins of the BCL-2 family that are overexpressed in various cancers, including lymphoid malignancies. Subtle changes in their structure significantly modified their activity on the target proteins. The two most active compounds are MCL-1 selective and bind in the BH3 binding groove of the protein. Complementary studies, by NMR and mass spectrometry analyses but also synthesis showed that they are covalent inhibitors of MCL-1, via the formation of a pyrrole adduct. In addition, cytotoxic assays revealed that these two compounds show a cytotoxic selectivity for BL2, a MCL-1/BCL-xL dependent cell line and induce apoptosis.
- Published
- 2021