Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1), Parkinson's Disease (Phase 1)
PF-05251749 is an inhibitor of Casein kinase 1 delta and epsilon (CK1δ and ε). It was being developed by Pfizer for the treatment of Alzheimer's disease, and is now owned by Biogen. It is taken by mouth.
CK1δ and ε are key regulators of the circadian clock, and are upregulated in AD brain. Early in AD, disruption of circadian cycles, including sleep, is thought to contribute to the accumulation of amyloid, and subsequent cognitive decline. Later in disease, changes in circadian and sleep cycles lead to abnormal late-day and nighttime activity, a major reason why people go into nursing homes.
Besides affecting circadian cycling, CK1δ and ε phosphorylate tau and are found in neurofibrillary tangles (Yasojima et al., 2000; Chen et al., 2017; Gu et al., 2019). CK1δ and ε also localize to granulovacuolar degeneration bodies, pathological protein assemblies found in the brains of people with AD and other neurodegenerative diseases (Wiersma et al., 2019; Riku et al., 2019).
No preclinical data has been published on PF-05251749; however, work with the Pfizer CK1 δ and ε dual inhibitor PF-670462 has been reported in two AD mouse models. In APP/PS1 mice, treatment with the inhibitor improved circadian rhythmicity and cognitive performance, while reducing brain amyloid (Sundaram et al., 2019). In 3X-Tg-AD mice, PF-670462 normalized alterations in hippocampal AD and clock-related pathways, including changes in proteins involved in synaptic plasticity and amyloid precursor protein processing. The compound also reduced working memory deficits and normalized circadian behaviors (Adler et al., 2019).
In 2015, Pfizer conducted a single-site, single-ascending-dose study in 32 healthy volunteers, assessing its propensity to induce movement disorders and affect mood and fatigue, as well as pharmacokinetics and exposure in CSF.
In March 2016, the company started an ascending-multiple-dose study of 50 to 900 mg daily of this compound in 97 healthy elderly volunteers at two sites in Florida. This trial also assessed suicidality and melatonin production, and expanded the number of pharmacokinetic measures. One arm administered PF-05251749 together with melatonin.
In January 2018, Pfizer announced it was ending its neurology research and development, including this compound.
In January 2020, Biogen acquired PF-05251749 (press release). The company announced plans to develop the drug for the treatment of sundowning in Alzheimer’s and irregular sleep-wake rhythm disorder in Parkinson’s, starting with a Phase 1b study in late 2020.
For all trials of this drug, see clinicaltrials.gov.
Last Updated: 11 Sep 2020
- Yasojima K, Kuret J, DeMaggio AJ, McGeer E, McGeer PL. Casein kinase 1 delta mRNA is upregulated in Alzheimer disease brain. Brain Res. 2000 May 19;865(1):116-20. PubMed.
- Chen C, Gu J, Basurto-Islas G, Jin N, Wu F, Gong CX, Iqbal K, Liu F. Up-regulation of casein kinase 1ε is involved in tau pathogenesis in Alzheimer's disease. Sci Rep. 2017 Oct 18;7(1):13478. PubMed.
- Gu J, Hu W, Tan X, Qu S, Chu D, Gong CX, Iqbal K, Liu F. Elevation of casein kinase 1ε associated with TDP-43 and tau pathologies in Alzheimer's disease. Brain Pathol. 2019 Aug 3; PubMed.
- Wiersma VI, van Ziel AM, Vazquez-Sanchez S, Nölle A, Berenjeno-Correa E, Bonaterra-Pastra A, Clavaguera F, Tolnay M, Musters RJ, van Weering JR, Verhage M, Hoozemans JJ, Scheper W. Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology. Acta Neuropathol. 2019 Dec;138(6):943-970. Epub 2019 Aug 27 PubMed.
- Riku Y, Duyckaerts C, Boluda S, Plu I, Le Ber I, Millecamps S, Salachas F, Brainbank NeuroCEB Neuropathology Network, Yoshida M, Ando T, Katsuno M, Sobue G, Seilhean D. Increased prevalence of granulovacuolar degeneration in C9orf72 mutation. Acta Neuropathol. 2019 Nov;138(5):783-793. Epub 2019 May 29 PubMed.
- Sundaram S, Nagaraj S, Mahoney H, Portugues A, Li W, Millsaps K, Faulkner J, Yunus A, Burns C, Bloom C, Said M, Pinto L, Azam S, Flores M, Henriksen A, Gamsby J, Gulick D. Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer's disease. Sci Rep. 2019 Sep 24;9(1):13743. PubMed.
- Adler P, Mayne J, Walker K, Ning Z, Figeys D. Therapeutic Targeting of Casein Kinase 1δ/ε in an Alzheimer's Disease Mouse Model. J Proteome Res. 2019 Sep 6;18(9):3383-3393. Epub 2019 Aug 6 PubMed.
No Available Further Reading