Discovery of potent chromone-based autotaxin inhibitors inspired by cannabinoids
Mathias Christophe Eymery1, Kim-Anh Nguyen2, Shibom Basu3
1European Molecular Biology Laboratory, EMBL Grenoble, 71 Avenue des Martyrs, 38000, Grenoble, France; Univ. Grenoble Alpes, INSERM U1039, LRB, 38000, Grenoble, France.
Abstract:
Autotaxin (ATX) is an enzyme primarily known for the production of lysophosphatidic acid. Being involved in the development of major human diseases, such as cancer and neurodegenerative diseases, the enzyme has been featured in multiple studies as a pharmacological target. We previously found that the cannabinoid tetrahydrocannabinol (THC) could bind and act as an excellent inhibitor of ATX. This study aims to use the cannabinoid scaffold as a starting point to find cannabinoid-unrelated ATX inhibitors, following a funnel down approach in which large chemical libraries sharing chemical similarities with THC were screened to identify lead scaffold types for optimization. This approach allowed us to identify compounds bearing chromone and indole scaffolds as promising ATX inhibitors. Further optimization led to MEY-003, which is characterized by the direct linkage of an N-pentyl indole to the 5,7-dihydroxychromone moiety. This molecule has potent inhibitory activity towards ATX-β and ATX-ɣ as evidenced by enzymatic studies and its mode of action was rationalized by structural biology studies using macromolecular X-ray crystallography.
Insights
Researchers identified novel, non-cannabinoid inhibitors of autotaxin (ATX), an enzyme linked to cancer and neurodegenerative diseases. The study optimized chromone and indole scaffolds, leading to a potent ATX inhibitor MEY-003.
Area of Science:
- Medicinal Chemistry
- Enzymology
- Structural Biology
Background:
- Autotaxin (ATX) is a key enzyme in lysophosphatidic acid production, implicated in diseases like cancer and neurodegeneration.
- ATX is a validated pharmacological target due to its role in major human pathologies.
- Previous work identified tetrahydrocannabinol (THC) as a potent ATX inhibitor.
Purpose of the Study:
- To discover novel, cannabinoid-unrelated inhibitors of autotaxin (ATX).
- To utilize a scaffold-hopping approach starting from the THC-ATX interaction.
- To identify and optimize lead compounds targeting ATX for therapeutic development.
Main Methods:
- Screening of large chemical libraries for compounds with structural similarity to THC.
- Structure-based drug design and lead optimization.
- Enzymatic assays and macromolecular X-ray crystallography to determine inhibitory activity and mechanism of action.
Main Results:
- Identification of chromone and indole scaffolds as promising ATX inhibitor classes.
- Optimization of lead compounds resulted in MEY-003, a potent ATX inhibitor.
- Structural studies elucidated the binding mode and rationalized the inhibitory activity of MEY-003 against ATX-β and ATX-ɣ.
Conclusions:
- Novel chromone and indole-based scaffolds are effective ATX inhibitors.
- MEY-003 represents a potent, structurally characterized ATX inhibitor with therapeutic potential.
- This study provides a foundation for developing new ATX-targeted therapies for associated diseases.
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