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Published on: June 30, 2023
Phenotypic Identification of a Novel Autophagy Inhibitor Chemotype Targeting Lipid Kinase VPS34
Lucas Robke1,2, Luca Laraia1, Marjorie A Carnero Corrales1,2
1Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.
Abstract:
Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small-molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring the formation of autophagy-induced puncta, indicating accumulation of the lipidated cytosolic protein LC3 on the autophagosomal membrane. Target identification and validation revealed that autophinib inhibits autophagy induced by starvation or rapamycin by targeting the lipid kinase VPS34.
Insights
Researchers discovered autophinib, a novel small-molecule inhibitor targeting VPS34. This compound effectively blocks autophagy, a cellular process implicated in cancer and neurological diseases, offering a new therapeutic avenue.
Area of Science:
- Cell Biology
- Molecular Medicine
- Drug Discovery
Background:
- Autophagy is a fundamental cellular process crucial for maintaining homeostasis and metabolism.
- Dysregulation of autophagy is linked to various diseases, including cancer and neurological disorders.
- Targeting autophagy presents a promising therapeutic strategy for these conditions.
Purpose of the Study:
- To discover and characterize novel small-molecule autophagy modulators.
- To identify a potent inhibitor with a unique chemical structure.
- To validate the mechanism of action for therapeutic development.
Main Methods:
- Phenotypic screening using an assay to detect autophagy-induced puncta (LC3 accumulation).
- Identification of small molecules that inhibit autophagy.
- Target identification and validation of the inhibitor's molecular target.
Main Results:
- Discovery of autophinib, a novel small-molecule autophagy inhibitor with a unique chemotype.
- Autophinib effectively inhibits autophagy induced by starvation and rapamycin.
- Target validation confirmed that autophinib targets the lipid kinase VPS34.
Conclusions:
- Autophinib is a potent inhibitor of autophagy via VPS34 targeting.
- This novel compound represents a promising lead for developing new therapeutics for autophagy-related diseases.
- Further investigation of autophinib is warranted for its potential in treating cancer and neurological disorders.
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