Advantages
- Unlike existing sleep disorder treatments such as melatonin receptor agonists and orexin receptor antagonists, CRY acts on the circadian clock itself to adjust its period and phase, making it possible to treat circadian rhythm disorders fundamentally.
- It has effects on not only the central clock but also the peripheral clock, making it possible to correct jet lag comprehensively.
- It can correct deviations in sleep-wake rhythms caused by chronic jet lag.
- Because CRY is not a GPCR, desensitization and resistance are less likely to occur.
- It can be administered orally and has central distribution.
Current Stage and Key Data
- Compound optimization and preclinical research.
- Oral administration of CRY1-A or CRY2-A to wild-type mice (50 mg/kg, once a day for 2 weeks) confirmed reversible control of circadian rhythms in sleep and wakefulness.
Partnering Model
- Currently seeking exclusive license partners for CRY1-A and CRY2-A.
- Feasibility studies available through CDA/MTA/option agreement/joint research agreement.
Background and Technology
The clock protein CRY plays a central role in the oscillation of the circadian clock and is responsible genes for human sleep rhythm disorders. Furthermore, Cry gene knockout mice show abnormalities in glucose metabolism. Therefore, CRY is expected to be a drug target for sleep rhythm disorders and glucose metabolism diseases.
We previously discovered a synthetic compound, a carbazole derivative KL001 that acts on both CRY1 and CRY2, inhibiting the degradation of CRY via the ubiquitin ligase FBXL3, activating CRY function, and extending the period of the circadian rhythm at the cellular and tissue levels. Furthermore, KL001 inhibited the activation of gluconeogenesis by glucagon stimulation in primary cultured mouse hepatocytes (*1).
We continued to search for compounds that selectively activate either CRY1 or CRY2 (*2), and have now developed CRY isoform-selective drug seed compounds CRY1-A and CRY2-A that can reach the brain via oral administration and regulate mammalian behavioral rhythms.
Principal Investigator
Tsuyoshi HIROTA (Institute of Transformative Bio-Molecules, Nagoya University, Tokai National Higher Education and Research System)
Reference and Patents
- *1) Hirota, T. et al. Science 337, 1094-1097 (2012).
*2) Miller, S. et al. Nature Chemical Biology 16, 676-685 (2020) - Patent pending (unpublished yet)
Project.BK-04911b