Journal
CHEMMEDCHEM
Volume 16, Issue 11, Pages 1788-1797Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100011
Keywords
BCL-2 proteins; MCL-1; cancer; covalent inhibitors; natural compounds; protein– protein interaction; Drimane sesquiterpenoids
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Funding
- University Paris-Saclay
- IDI 2016 project [ANR-11-IDEX-0003-02]
- Agence Nationale de la Recherche (CEBA) [ANR-10-LABX-25-01]
- IR-RMN-THC FR 3050 CNRS
- Ligue Contre le Cancer (Calvados committee, NEMIBLY Project)
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Drimane sesquiterpenoid dialdehydes are natural compounds that act as potent inhibitors of MCL-1 and BCL-xL, two overexpressed proteins in various cancers, by covalently inhibiting MCL-1 and inducing apoptosis, showing selectivity for MCL-1/BCL-xL-dependent cell lines.
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.
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