JNJ-6204
[CAS# 2765264-50-2]

Identification

• Classification: Chemical reagent >> Deuterated reagent
• Name: JNJ-6204
• Synonyms: 2-(5-fluoropyridin-2-yl)-3-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6,6-bis(trideuteriomethyl)-4,7-dihydropyrazolo[5,1-c][1,4]oxazine
• Molecular Formula: C₁₉H₁₁D₆FN₆O
• Molecular Weight: 370.41
• CAS Registry Number: 2765264-50-2
• SMILES: [2H]C([2H])([2H])C1(CN2C(=C(C(=N2)C3=NC=C(C=C3)F)C4=C5C=NNC5=NC=C4)CO1)C([2H])([2H])[2H]

Discovory and Applicatios

JNJ-6204 is a selective small-molecule inhibitor of casein kinase 1 delta (CSNK1D) and casein kinase 1 epsilon (CSNK1E), members of the casein kinase 1 (CK1) family of serine/threonine kinases. These enzymes are integral to the regulation of various biological processes including the circadian rhythm, Wnt signaling, DNA repair, and cell cycle progression. The development of JNJ-6204 was aimed at creating a potent and selective inhibitor that could be used to probe the role of CK1 isoforms in disease-relevant cellular functions, particularly those involving dysregulation of circadian or proliferative pathways.

The compound emerged from targeted medicinal chemistry efforts to address the need for greater isoform selectivity and pharmacological precision. In biochemical assays, JNJ-6204 demonstrates nanomolar potency against CSNK1D and moderate inhibition of CSNK1E, indicating a degree of selectivity that enables distinct pharmacological interrogation of these kinases. Its design incorporates structural features that optimize ATP-competitive binding to the kinase domain of CSNK1D, allowing for high affinity and specificity while minimizing off-target interactions with other kinases.

Application of JNJ-6204 in cellular models has helped elucidate the functional contributions of CK1 isoforms to circadian timekeeping. CSNK1D and CSNK1E are key regulators of clock protein phosphorylation, which determines the stability, localization, and activity of core circadian proteins such as PER and CRY. Inhibition of these kinases with JNJ-6204 leads to phase shifts and altered period lengths in circadian oscillations, confirming their central role in circadian rhythm modulation. This makes JNJ-6204 a useful chemical probe for chronobiological research.

Beyond its utility in circadian studies, JNJ-6204 has been explored in the context of proliferative disorders. CK1 isoforms have been implicated in oncogenic signaling pathways, particularly in relation to Wnt/β-catenin activation. By modulating CK1 activity, JNJ-6204 may influence the phosphorylation state and degradation of β-catenin, potentially impacting cell proliferation in tumor models. Early-stage research using JNJ-6204 has investigated these effects, but further preclinical data are needed to assess its potential as a therapeutic agent.

The compound has also shown promise as a research tool in neurobiology, given the involvement of CK1 in tau phosphorylation and neurodegenerative disease mechanisms. Inhibition of CSNK1D with JNJ-6204 reduces tau hyperphosphorylation in some cellular models, suggesting that targeting this kinase might influence the progression of tauopathies such as Alzheimer's disease. However, in vivo studies and comprehensive pharmacokinetic data are still limited.

JNJ-6204 is typically formulated for in vitro use, with properties that support high cellular permeability and stability under experimental conditions. Its activity profile allows for controlled inhibition of CK1-mediated phosphorylation events, which is particularly valuable in dissecting temporal or spatial aspects of kinase signaling in live cells.

Although JNJ-6204 has not yet advanced into clinical development, its high selectivity and defined mechanism of action make it a powerful investigative compound for kinase biology. As the role of CK1 isoforms becomes better understood in disease pathogenesis, selective inhibitors like JNJ-6204 may inform the design of future therapeutic candidates targeting these kinases with greater precision and safety.

References

2024. Structure-Based Optimization of Selective and Brain Penetrant CK1d Inhibitors for the Treatment of Circadian Disruptions. ACS Medicinal Chemistry Letters, 15(4).
DOI: 10.1021/acsmedchemlett.3c00523