PF-670462 dihydrochloride | Casein kinase 1δ/ε inhibitor

PF-670462 (950912-80-8) is a potent inhibitor of casein kinase 1ε/δ (CK1ε, IC₅₀ = 7.7 nM; CK1δ, IC₅₀ = 14 nM).¹ It is a circadian clock modifier that caused robust phase delays in rats¹ and Cynomolgus monkeys². PF-670462 caused nuclear retention of the clock protein PER resulting in period lengthening in a phase-specific manner that was dependent on CK1δ inhibition and not CK1ε.³ It improved cognitive performance and reduced amyloid load in various mouse models of Alzheimer’s disease.^4-6 PF-670462 slowed the progression of and increased survival of chronic lymphocytic leukemia in mice alone and in combination with Ibrutinib.⁷

References/Citations:

1. Badura et al. (2007), An Inhibitor of Casein Kinase Iε Induces Phase Delays in Circadian Rhythms under Free-Running and Entrained Conditions; J. Pharmacol. Exp. Ther. 322 730
2. Sprouse et al. (2009), Inhibition of casein kinase I epsilon/delta produces phase shifts in the circadian rhythms of Cynomolgus monkeys; Psychopharmacology (Berl) 204 735
3. Meng et al. (2010), Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes; Proc. Natl. Acad. Sci. USA 107 15240
4. Adler et al. (2019), Therapeutic Targeting of Casein Kinase 1δ/ε in an Alzheimer’s Disease Mouse Model; Proteome Res. 18 3383
5. Sundaram et al. (2019), Inhibition of casein kinase 1δ improves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer’s Disease; Sci. Rep 9 13743
6. Mahoney et al. (2021), Inhibition of casein kinase 1δ/ε improves cognitive performance in adult C57BL/6J mice; Sci. Rep. 11 4746
7. Janovska et al. (2018), Casein kinase 1 is a therapeutic target on chronic lymphocytic leukemia; Blood 131 1206