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Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL‐1
Author(s) -
Daressy Florian,
Malard Florian,
Seguy Line,
Guérineau Vincent,
Apel Cécile,
Dumontet Vincent,
Robert Aude,
Groo AnneClaire,
Litaudon Marc,
Big Jérôme,
Desrat Sandy,
MalzertFréon Aurélie,
Wiels Joëlle,
Lescop Ewen,
Roussi Fanny
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100011
Subject(s) - chemistry , stereochemistry , covalent bond , adduct , cytotoxic t cell , cytotoxicity , nuclear magnetic resonance spectroscopy , selectivity , mode of action , biochemistry , combinatorial chemistry , in vitro , organic chemistry , catalysis
Drimane sesquiterpenoid dialdehydes are natural compounds with antiproliferative properties. Nevertheless, their mode of action has not yet been discovered. Herein, we demonstrate 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 spectroscopy and mass spectrometry analyses, but also synthesis, showed that they covalently inhibit MCL‐1 though 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.