Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL‐1

• DOI: 10.1002/cmdc.202100011
• Publication Date: 2021-03-05T09:06:44Z
• Authors: Florian Daressy; Florian Malard; Line Seguy; Vincent Guérineau; Cécile Apel; Vincent Dumontet; Aude Robert; Anne‐Claire Groo; Marc Litaudon; Jérôme Bignon; Sandy Desrat; Aurélie Malzert‐F...; Joëlle Wiels; Ewen Lescop; Fanny Roussi
• Keywords: Polycyclic Sesquiterpenes; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; 610; Antineoplastic Agents; Apoptosis; [CHIM.THER]Chemical Sciences/Medicinal Chemistry; 04 agricultural and veterinary sciences; 540; 3. Good health; Structure-Activity Relationship; 0404 agricultural biotechnology; Protein Domains; Cell Line, Tumor; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Drug Screening Assays, Antitumor; 0405 other agricultural sciences; Cell Proliferation; bcl-2-Associated X Protein

AbstractDrimane 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.