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Identification and further development of potent TBK1 inhibitors
André Richters1, Debjit Basu, Julian Engel
1Department of Chemistry and Chemical Biology, Technical University of Dortmund , Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
Abstract:
The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related signaling and its relevance in tumor progression. Herein, we undertake the activity-based screening for unique inhibitors of TBK1 and their subsequent optimization. Initial screening approaches identified a selection of TBK1 inhibitors that were optimized using methods of medicinal chemistry. Variations of the structural characteristics of a representative 2,4,6-substituted pyrimidine scaffold resulted in improved potency. Prospective use as tool compounds or basic contributions to drug design approaches are anticipated for our improved small molecules.
Insights
Researchers identified novel inhibitors for TBK1 (TANK-binding kinase 1), a protein kinase involved in tumor migration and progression. These optimized small molecules offer potential as research tools and in drug design for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The serine/threonine kinase TBK1 plays a critical role in signaling pathways that drive tumor cell migration and overall tumor progression.
- There is a significant need for novel therapeutic agents and chemical probes to investigate TBK1-mediated signaling in cancer.
Purpose of the Study:
- To identify and optimize novel small molecule inhibitors of TBK1.
- To develop potential tool compounds for studying TBK1 signaling in tumor progression.
- To contribute to the drug design process for cancer therapeutics targeting TBK1.
Main Methods:
- Activity-based screening was employed to identify initial TBK1 inhibitors.
- Medicinal chemistry approaches were used for the optimization of identified compounds.
- Structure-activity relationships were explored using a 2,4,6-substituted pyrimidine scaffold.
Main Results:
- A selection of TBK1 inhibitors was successfully identified through screening.
- Optimization efforts led to improved potency of the identified inhibitors.
- Structural modifications of the pyrimidine scaffold enhanced inhibitor efficacy.
Conclusions:
- The developed small molecules serve as valuable tool compounds for further research into TBK1 signaling.
- These optimized inhibitors represent a foundation for future drug design strategies targeting TBK1 in cancer.
