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Science 337 (6098): 1094-1097

Copyright © 2012 by the American Association for the Advancement of Science

Identification of Small Molecule Activators of Cryptochrome

Tsuyoshi Hirota,1,7 Jae Wook Lee,2 Peter C. St. John,3 Mariko Sawa,1 Keiko Iwaisako,4 Takako Noguchi,5 Pagkapol Y. Pongsawakul,1 Tim Sonntag,1 David K. Welsh,5,6 David A. Brenner,4 Francis J. Doyle, III,3 Peter G. Schultz,2,* Steve A. Kay1,7,*

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.

1 Division of Biological Sciences and Center for Chronobiology, University of California San Diego, La Jolla, CA 92093, USA.
2 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
3 Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
4 Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
5 Department of Psychiatry and Center for Chronobiology, University of California San Diego, La Jolla, CA 92093, USA.
6 Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
7 San Diego Center for Systems Biology, University of California San Diego, La Jolla, CA 92093, USA.

* To whom correspondence should be addressed. E-mail: skay{at}ucsd.edu (S.A.K.); schultz{at}scripps.edu (P.G.S.)

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