A Small Molecule Modulates Circadian Rhythms through Phosphorylation of the Period Protein

This paper is a cool example of one advantage of Chemical Biology over Genetics. They reported the application in behavioral studies of the small molecule inhibitor of CKIdelta to overcome the limitation of lethality induced by CKIdelta knock-down mutations.

They identified the small molecule LH846 after a Luciferase cell-based assay of 500 000 compounds. The probe was then functionalized with a PEG linker and used in pull-down assays, they identified casein kinase 1 delta (CKIdelta) as the target. This is a known protein kinase that regulates the circadian clock. LH846 is a relatively potent and selective CKIdelta inhibitor that could provide insights into the role of circadian rhythms as well as new treatments for circadian disorders.