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Published on: September 28, 2017
Small-Molecule Kinase Inhibitors Modulating Circadian Rhythms
Irene Castellino1,2, Manuela Bartolini2, Rudolf Andrys1
1Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic.
Abstract:
The circadian clock mechanism generates 24-h rhythms crucial for regulating various physiological processes, and its dysregulation has been implicated in numerous diseases. In cells, the circadian clock operates through a transcriptional-translational feedback loop, where phosphorylation plays a pivotal role in maintaining accurate circadian rhythms. Consequently, kinase inhibitors have emerged as promising targets for modulating the circadian clock and potentially treating circadian-related diseases. This review aims to provide an overview of the current state-of-the-art of kinase inhibitors with effects on the mammalian circadian clock. By highlighting promising targets and addressing the limitations of existing inhibitors, this review intends to provide a guide for future research efforts towards the development of novel compounds for the treatment of circadian-related disorders. Furthermore, it highlights the critical discrepancy between in vitro activity and in vivo effectiveness, emphasizing the critical need for rigorous in vivo validation to translate the therapeutic potential of kinase inhibitors into effective treatments for these disorders.
Insights
Kinase inhibitors show promise for treating circadian clock disorders by targeting phosphorylation in the cellular feedback loop. Further research is needed to bridge the gap between lab results and effective in vivo treatments.
Area of Science:
- Biochemistry
- Chronobiology
- Pharmacology
Background:
- The circadian clock regulates vital physiological processes via a transcriptional-translational feedback loop.
- Phosphorylation is critical for maintaining circadian rhythm accuracy within cells.
- Dysregulation of the circadian clock is linked to various diseases.
Purpose of the Study:
- To review current kinase inhibitors affecting the mammalian circadian clock.
- To identify promising therapeutic targets and limitations of existing inhibitors.
- To guide future research for novel treatments of circadian-related disorders.
Main Methods:
- Literature review of kinase inhibitors and their effects on the circadian clock.
- Analysis of phosphorylation's role in circadian rhythm regulation.
- Evaluation of in vitro activity versus in vivo effectiveness.
Main Results:
- Kinase inhibitors are potential modulators of the circadian clock.
- Significant discrepancies exist between in vitro and in vivo efficacy of inhibitors.
- Specific targets and limitations of current compounds are highlighted.
Conclusions:
- Kinase inhibitors offer a promising avenue for treating circadian rhythm disorders.
- Rigorous in vivo validation is essential to translate therapeutic potential into clinical applications.
- Further development is needed to overcome limitations and ensure effective treatments.
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