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Identification of Small Molecule Activators of Cryptochrome

Identification of Small Molecule Activators of Cryptochrome

Tsuyoshi Hirota, Jae Wook Lee, Peter C St John, Mariko Sawa, Keiko Iwaisako, Takako Noguchi, Pagkapol Y Pongsawakul, Tim Sonntag, David K Welsh, David A Brenner, Francis J Doyle 3rd, Peter G Schultz, Steve A Kay

Science. 2012 Aug 31;337(6098):1094-7.

PMID: 22798407

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP309928481	KL001		309928-48-1	Price

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