Abstract
Impairment of the circadian clock has been associated with numerous disorders, including metabolic disease. Although small molecules that modulate clock function might offer therapeutic approaches to such diseases, only a few compounds have been identified that selectively target core clock proteins. From an unbiased cell-based circadian phenotypic screen, we identified KL001, a small molecule that specifically interacts with cryptochrome (CRY). KL001 prevented ubiquitin-dependent degradation of CRY, resulting in lengthening of the circadian period. In combination with mathematical modeling, our studies using KL001 revealed that CRY1 and CRY2 share a similar functional role in the period regulation. Furthermore, KL001-mediated CRY stabilization inhibited glucagon-induced gluconeogenesis in primary hepatocytes. KL001 thus provides a tool to study the regulation of CRY-dependent physiology and aid development of clock-based therapeutics of diabetes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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3T3 Cells
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Amino Acid Sequence
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Animals
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Carbazoles / chemistry
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Carbazoles / isolation & purification
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Carbazoles / pharmacology*
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Cell Line, Tumor
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Circadian Clocks / drug effects*
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Cryptochromes / agonists*
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Cryptochromes / metabolism
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Gluconeogenesis / drug effects
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Gluconeogenesis / genetics
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Glucose-6-Phosphatase / genetics
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HEK293 Cells
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Liver / cytology
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Liver / drug effects
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Liver / metabolism
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Mice
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Molecular Sequence Data
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Phosphoenolpyruvate Carboxykinase (GTP) / genetics
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Protein Stability / drug effects
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Proteolysis / drug effects
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Small Molecule Libraries*
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Sulfonamides / chemistry
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Sulfonamides / isolation & purification
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Sulfonamides / pharmacology*
Substances
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CRY1 protein, human
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CRY2 protein, human
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Carbazoles
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Cryptochromes
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KL001
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Small Molecule Libraries
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Sulfonamides
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Glucose-6-Phosphatase
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Phosphoenolpyruvate Carboxykinase (GTP)