Therapeutic Potential of Silmitasertib Observed in Huntington Disease Mouse Model

Author(s):

Key Takeaways

Silmitasertib (CX4945) shows promise in reducing mHTT aggregation and improving motor function in HD mouse models.
CK2 inhibition emerges as a potential therapeutic strategy for HD, with CX4945 reducing neuropathology in the striatum.
Further research is needed to explore CK2α and CK2α’ subunits' roles in HD pathology and develop more selective inhibitors.
CK2α’ may influence protein homeostasis, inflammation, and synaptic gene expression, suggesting targeted inhibition could alleviate HD symptoms.

A recent study reported that silmitasertib, an investigational drug currently in development for cancer, may help reduce motor deficits and neuropathology in a Huntington disease.

Ross Pelzel

(Credit: University of Minnesota)

Newly presented preclinical research suggests that silmitasertib (CX4945), an FDA-designated orphan drug for cancer, may offer therapeutic benefits for Huntington disease (HD) by reducing mutant huntingtin (mHTT) aggregation and improving motor function in a mouse model.¹ The findings build on prior research implicating CK2 in HD pathology, suggesting that pharmacological inhibition of CK2 may be a viable therapeutic strategy.

In the study, researchers administered CX4945 via gavage in both wild-type and zQ175 HD mice. All told, results showed that CX4945-treated HD mice had significantly improved motor function compared with untreated controls and that CX4945 reduced mHTT aggregation and neuropathology in the striatum. Further analysis revealed that CX4945 enhanced astrocytic uptake of mHTT aggregates and altered astrocyte subtype distribution and physiological characteristics.

These findings were recently presented at the 2025 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), held April 1-5 in Vienna, Austria, by lead author Ross Pelzel, a student in the graduate program in neuroscience at University of Minnesota. HD is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene, leading to progressive cognitive, motor, and psychiatric symptoms. A key pathological feature of the disease is the selective degeneration of striatal neurons and accompanying astrocytic changes.

CK2 inhibition is emerging as a potential therapeutic strategy not only for HD but also for other neurodegenerative disorders. However, gaps in knowledge and conflicting findings may need to be addressed to better understand its efficacy in HD. Key areas for further research could include using genetic approaches to assess the specific effects of targeting CK2α or CK2α’ in vivo, assessing the impact of CK2 depletion across multiple HD mouse models, and developing more selective inhibitors for CK2α’ and CK2α to determine their role in reducing mHTT toxicity.²

Evidence suggests that CK2α’ contributes to HD pathology by influencing protein homeostasis, inflammation, synaptic gene expression, synucleinopathy, and motor function. Although pharmacological CK2 inhibition has been shown to affect HTT phosphorylation, it remains unclear whether different CK2 catalytic subunits play distinct roles in this process. Given this uncertainty, researchers noted in a published review that specifically targeting CK2α’ may be a more effective therapeutic approach, with the potential to provide long-term benefits in alleviating multiple HD-related symptoms.²

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REFERENCES
1. Pelzel R, White A., Yu D, et al. Repurposing an anticancer agent for the treatment of Huntington's disease. Presented at: 2025 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD); April 1-5. Vienna, Austria. Abstract 2399.
2. White A, McGlone A, Gomez-Pastor R. Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington's Disease. Biomedicines. 2022;10(8):1979. Published 2022 Aug 15. doi:10.3390/biomedicines10081979