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Expression, Purification, Crystallization, and Enzyme Assays of Fumarylacetoacetate Hydrolase Domain-Containing Proteins
Published on: June 20, 2019
Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory
Tiziana Masini1, Barbara Birkaya2, Simon van Dijk1
1a Stratingh Institute for Chemistry, University of Groningen , Groningen , The Netherlands.
Abstract:
The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.
Insights
Researchers identified new furoate and thenoate derivatives as pyruvate dehydrogenase kinase (PDK) inhibitors. These compounds target the pyruvate site, offering a potential alternative to dichloroacetic acid (DCA) for cancer metabolism research and therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer metabolism has re-emerged as a critical therapeutic target in oncology.
- Pyruvate dehydrogenase kinase (PDK) inhibition shows significant promise for cancer treatment.
- Dichloroacetic acid (DCA) is a known PDK inhibitor but has limitations including neurotoxicity and high concentration requirements.
Purpose of the Study:
- To identify novel allosteric inhibitors of PDK that bind to the pyruvate site.
- To explore alternatives to DCA with improved safety and efficacy profiles.
- To validate the pyruvate regulatory pocket of PDK as a druggable target.
Main Methods:
- Utilized saturation-transfer difference NMR spectroscopy to identify potential inhibitors.
- Employed enzymatic assays to confirm PDK inhibitory activity.
- Applied computational methods to guide inhibitor design and understand binding interactions.
Main Results:
- Identified furoate and thenoate derivatives as novel allosteric PDK2 inhibitors.
- These compounds bind to the pyruvate site of PDK, similar to DCA.
- Demonstrated the potential for these derivatives to overcome DCA's limitations.
Conclusions:
- The pyruvate regulatory pocket of PDK is a viable and druggable target for cancer therapy.
- Furoate and thenoate derivatives represent promising new chemical entities for targeting cancer metabolism.
- This research provides a foundation for developing safer and more effective PDK-targeting cancer drugs.
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