KL001

KL-001 (309928-48-1) is a novel tool that specifically interacts with cryptochrome (CRY) preventing its ubiquitin-dependent degradation resulting in lengthening of the circadian period. KL-001-mediated CRY stabilization inhibits glucagon-induced gluconeogenesis in primary hepatocytes.1Binds to the FAD-binding pocket of CRY2 as determined by co-crystal structure.2KL-001 induces an increase in period along with simultaneous reduction in amplitude of circadian reporter expression3 in mammalian cells.

KL001 is a small molecule that specifically interacts with cryptochrome (CRY). KL001 prevented ubiquitin-dependent degrdation of CRY, resulting in lengthening of the circadian period. KL001-mediated CRY stabilization inhibited glucagon-induced gluconeogenesis in primary hepatocytes making it a tool to study the regulation of CRY-dependent physiology and aid development of clock-based therapeutics of diabetes.

KL001 stabilizes cryptochrome (CRY), preventing ubiquitin-dependent degradation. CRY proteins are part of a feedback loop, acting as transcription repressors to inhibit CLOCK-BMAL1 components of the circadian clock. KL001 stabilization of CRY proteins results in lengthening of the circadian period, and also inhibited glucagon-induced gluconeogenesis in primary hepatocytes. Other compounds affecting circadian rhythms include Casein kinase I (CKI) inhibitors such as longdaysin (Sigma Prod. No. SML0127) and synthetic ligands for the nuclear receptors REV-ERB such as SR8278 (Sigma Prod. No. S9576), but KL001 appears to be the first small molecule that specifically acts on CRY proteins.

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[1] TSUYOSHI HIROTA, III  Steve A K  Peter G Schultz. Identification of Small Molecule Activators of Cryptochrome[J]. Science, 2012, 337 6098. DOI:10.1126/science.1223710
[2] SHANNON NANGLE  Ning Z  Weiman Xing. Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase[J]. Cell Research, 2013, 23 12: 1417-1419. DOI:10.1038/cr.2013.136
[3] PETER C ST JOHN. Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111 5: 2040-2045. DOI:10.1073/pnas.1323618111