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TAK1 inhibition in the DFG-out conformation
Iain Kilty1, Martin P Green, Andrew S Bell
1Pfizer World Wide Research and Development, Ramsgate Road, Sandwich, CT13 9NJ, UK; BioTherapeutics Research and Development, Pfizer, Cambridge, MA, 02140, USA.
Chemical Biology & Drug Design
|June 11, 2013
Summary
Researchers developed a novel inhibitor targeting the kinase TAK1 in its DFG-out state. This molecule also inhibits p38 kinase, showing potent anti-inflammatory effects in cell-based assays.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- Transforming growth factor-beta-activated kinase 1 (TAK1) is a key regulator in inflammatory signaling pathways.
- Targeting kinases in specific conformations, like the DFG-out state, can lead to more selective inhibitors.
Purpose of the Study:
- To discover and characterize the first inhibitor of TAK1 that binds to the DFG-out conformation.
- To develop a dual inhibitor of p38 and TAK1 with anti-inflammatory properties.
Main Methods:
- Kinase-targeted screening assays were employed to identify potential inhibitors.
- Structure-based drug design principles were utilized to optimize lead compounds.
- Cell-based assays were used to evaluate anti-inflammatory activity.
Main Results:
- The study disclosed the first inhibitor of TAK1 that binds in the DFG-out conformation.
- A novel molecule was designed exhibiting dual inhibition of p38 and TAK1.
- The developed molecule demonstrated significant anti-inflammatory activity in cellular models.
Conclusions:
- A novel DFG-out selective TAK1 inhibitor was successfully developed.
- Dual inhibition of p38 and TAK1 represents a promising strategy for anti-inflammatory drug development.
- This work provides a foundation for further research into TAK1 and p38 targeted therapies.
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