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Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL-1
Florian Daressy1,2,3, Florian Malard1, Line Seguy4
1Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, Avenue de la terrasse, 91198, Gif-sur-Yvette Cedex, France.
Chemmedchem
|March 5, 2021
Summary
Drimane sesquiterpenoids are natural compounds that inhibit MCL-1 and BCL-xL proteins, crucial in cancer. These compounds covalently bind MCL-1, inducing cancer cell death and apoptosis.
Area of Science:
- Natural product chemistry
- Cancer biology
- Molecular pharmacology
Background:
- Drimane sesquiterpenoid dialdehydes exhibit antiproliferative effects.
- The precise mechanism of action for these compounds remains largely unknown.
- MCL-1 and BCL-xL, anti-apoptotic proteins of the BCL-2 family, are frequently overexpressed in various cancers, particularly lymphoid malignancies.
Purpose of the Study:
- To elucidate the molecular mechanism underlying the antiproliferative activity of drimane sesquiterpenoid dialdehydes.
- To identify specific BCL-2 family proteins targeted by these natural compounds.
- To investigate the structure-activity relationships of drimanes concerning their inhibitory potential.
Main Methods:
- Inhibition assays to assess the activity of drimanes against MCL-1 and BCL-xL.
- NMR spectroscopy and mass spectrometry to analyze compound binding and adduct formation.
- Chemical synthesis to create and test structural variants of drimanes.
- Cytotoxic assays using cancer cell lines, including a MCL-1/BCL-xL-dependent line (BL2).
Main Results:
- Several drimanes were identified as potent inhibitors of MCL-1 and BCL-xL.
- Structural modifications significantly impacted the inhibitory activity and selectivity.
- The two most potent compounds demonstrated selectivity for MCL-1, binding to its BH3 groove.
- Evidence of covalent inhibition of MCL-1 via pyrrole adduct formation was established through spectroscopic and synthetic analyses.
- These selective compounds induced apoptosis and exhibited cytotoxicity specifically in the BL2 cell line.
Conclusions:
- Drimane sesquiterpenoid dialdehydes are effective covalent inhibitors of MCL-1.
- Their mechanism involves binding to the BH3 groove and forming a pyrrole adduct with MCL-1.
- These compounds display selective cytotoxicity against cancer cells dependent on MCL-1/BCL-xL.
- This study reveals a novel mode of action for drimanes with potential therapeutic implications in cancer treatment.
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