1. Systems approach reveals photosensitivity and PER2 level as determinants of clock‐modulator efficacy
APF‐670 inhibits the phosphorylation of PER by CK1δ/ε (i) and delays the circadian phase, which is counterbalanced by light (ii). Thus, daily dosing leads to continually accumulating phase delay in DD and constant stable phase delay in LD. BMeasured free PF‐670 exposure in the brain tissue of mice and NHPs. Drug exposure in NHPs after administration of 10 mpk PF‐670 (AUC = 3.6 μM·h) is ˜7‐fold higher than that in mice given 32 mpk PF‐670 (AUC = 0.5 μM·h) (n = 2–3; mean ± SEM). The mouse data are adopted from (Kim et al, ). C, DDouble‐plotted actograms of NHPs’ activity for 16 days. NHPs were treated with 10 mpk PF‐670 for 3 consecutive days at the same solar time of day: 4 pm for the DD experiment (C) and 4:30 pm (ZT11) for the LD experiment (D), respectively, which are highlighted as red lines. White and black rectangles indicate the times of light going on and off (LD 12:12). E, FPhase delay induced by the 3‐day dosing under DD (E) or LD (F). The phase of activity onset in NHPs (10 mpk) is more delayed than that in mice (32 mpk) under DD (E), but not under LD (F) (n = 3–8; P = 0.03, one‐way analysis of variance (ANOVA); n.s., no significant difference). Veh denotes vehicle. The error bars represent mean ± SEM. The mouse data are adopted from (Kim et al, ). GThe quantification of (E) and (F) indicates that light has a stronger attenuating effect on the PF‐670‐induced phase delay in NHPs than in mice (n = 5–8; mean ± SEM; P = 0.036, two‐way ANOVA).
IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER.
Mol Syst Biol, Volume: 15, Issue: 7, First published: 08 July 2019, DOI: ( /msb )