ISX-9 potentiates CaMKII delta-mediated BMAL1 activation to enhance circadian amplitude

Circadian dysregulation associates with numerous diseases including metabolic dysfunction, sleep disorder, depression and aging. Given that declined circadian amplitude is a trait commonly found with compromised health, interventions that design in precluding circadian amplitude from dampening will aid to mitigate complex, circadian-related diseases. Here we identify a neurogenic small molecule ISX-9 that is able to support persistent and higher amplitude of circadian oscillations. ISX-9 improves diurnal metabolic rhythms in middle-aged mice. Moreover, the ISX-9-treated mice show better sleep homeostasis with increased delta power during the day time and higher locomotive activity in the dark period. ISX-9 augments CaMKII delta expression and increases BMAL1 activity via eliciting CaMKII delta-mediated phosphorylation on BMAL1 residues S513/S515/S516, accordingly composes a positive feedback effect on enhancing circadian amplitude. CaMKII delta-targeting, and the use of ISX-9 may serve as decent choices for treating circadian-related disorders. Circadian modulators that exert amplitude-enhancing activity using highthroughput compound screening of small molecules identifies ISX-9, which is shown to augment CaMKII delta expression, increasing BMAL1 activity via CaMKII delta-dependent phosphorylation.