idneitification of small molecule activators of cryptochrome
- idneitification of small molecule activators of cryptochrome
- Tsuyoshi Hirota; 이재욱; Peter C. St. John; Mariko Sawa; Keiko Iwaisako; Takako Noguchi; Pagkapol Y. Pongswakul; Tim Sonntag; David Welsh; David A. Brenner; Francis J. Doyle III; Peter G. Schultz; Steve A. Kay
- Issue Date
- VOL 337, NO 31, 1094-1097
- 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.
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