Early lead optimisation of novel potassium channel inhibitors for the development of treatments for KCNT1-related epilepsy

Project title

Early lead optimisation of novel potassium channel inhibitors for the development of treatments for KCNT1-related epilepsy

Description

External Co-Investigators

Dr Martin McPhillie, School of Chemistry

Project Description

Severe drug-resistant childhood epilepsy is caused by alterations in a protein in the brain named KCNT1 and is thought to affect around 1 in 300,000 births worldwide. Patients can experience seizures in the first months of life and lead to serious disabilities and even death in childhood. Current treatment for KCNT1 epilepsy only provides mild relief of symptoms and uses a number of experimental medications which must be personalised for the individual and are often poorly tolerated. Critically, with many patients, no therapeutic benefit is achieved.  We have been addressing this unmet clinical need by identifying novel chemicals that bind directly to the altered KCNT1 protein to restore its correct function. The objective of the proposed research is to optimise their chemical properties to make them suitable for ‘in-the-body' evaluation as potential medicines.  Presently, there are no effective treatments for this rare, but severe childhood neurological condition. If successful, we will have the basis of a drug that could be used to treat the source of KCNT1-associated conditions to prevent seizures and secondary neurological impairments. This new treatment may also prove to have beneficial effects in other drug-resistant epilepsies.

Impact

If successful, we will have a compound ready for in vivo efficacy and pharmacokinetic evaluation as a potential treatment for KCNT1-associated conditions to prevent seizures and secondary neurological impairments. Recent discussions with the KCNT1 Epilepsy Foundation showed that the families and carers of patients with KCNT1-associated Epilepsy view reducing seizure burden as their primary priority for a treatment. This new treatment may also prove to have beneficial effects in other drug-resistant epilepsies.

Publications and outputs

Caseley, E. A.; Simmons, K. J.; Cole, B. A.; Flynn, A. J.; Muench, S. P.; Lippiat, J. D.  Large-Scale Structure-Based Virtual Screening Identifies Diverse KNa1.1 (KCNT1) Potassium Channel Inhibitors. Eur J Med Chem 313:118906 Article number 118906 Apr 2026

Ricos MG, Cole BA, Hussain R, Rychkov GY, Shaukat Z, Pilati N, Muench SP, Simmons KJ, Dibbens LM, Lippiat JD. Identification of New KCNT1-Epilepsy Drugs by In Silico, Cell, and Drosophila Modeling. Annals of Neurology. (2025) Sept 13. https://doi.org/10.1002/ana.78031