Identification of small molecule activators of cryptochrome.
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.
Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Tsuyoshi
T
Hirota
Jae Wook
JW
Lee
Peter C
PC
St John
Mariko
M
Sawa
Keiko
K
Iwaisako
Takako
T
Noguchi
Pagkapol Y
PY
Pongsawakul
Tim
T
Sonntag
David K
DK
Welsh
David A
DA
Brenner
Francis J
FJ
Doyle
Peter G
PG
Schultz
Steve A
SA
Kay
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000187:drug effects*; D056931:Cryptochromes / Q000819:agonists* / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005952:Glucose-6-Phosphatase / Q000235:genetics; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
C538963:CRY1 protein, human; C538966:CRY2 protein, human; D002227:Carbazoles; D056931:Cryptochromes; C574808:KL001; D054852:Small Molecule Libraries; D013449:Sulfonamides; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)