Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Science. 2012 Aug 31;337(6098):1094-7. doi: 10.1126/science.1223710. Epub 2012 Jul 12.
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.
生物钟功能障碍与许多疾病有关，包括代谢疾病。虽然调节生物钟功能的小分子可能为治疗这些疾病提供了方法，但只有少数几种化合物被确定为能选择性靶向核心生物钟蛋白。通过一个无偏的基于细胞的生物钟表型筛选，我们发现了 KL001，这是一种能特异性与隐花色素（CRY）相互作用的小分子。KL001 阻止了 CRY 的泛素依赖性降解，导致生物钟周期延长。通过与数学模型相结合，我们使用 KL001 的研究表明，CRY1 和 CRY2 在调节周期方面具有相似的功能作用。此外，KL001 介导的 CRY 稳定抑制了原代肝细胞中胰高血糖素诱导的糖异生。因此，KL001 为研究 CRY 依赖性生理的调节提供了工具，并有助于开发基于时钟的糖尿病治疗方法。
