VU0935685: a novel structurally distinct inhibitor of SLACK channels

Malignant Migrating Partial Seizure of Infancy (MMPSI) is a severe, rare form of infantile epilepsy characterized by pharmacoresistant seizures and significant cognitive impairments. This devastating neurological disorder typically manifests within the first six months of life, often leading to profound developmental delays and, in 25% of cases, mortality within the first year. Sadly, to date, no broadly effective and safe drug therapy has been approved for the treatment of MMPSI.

Previous studies have linked MMPSI to multiple gain-of-function (GOF) mutations in the KCNT1 gene, encoding the SLACK potassium channel (also known as KNa1.1 or Slo2.2). SLACK is a member of the Slo family of K+ channels and is a critical regulator of neuronal excitability within the central nervous system (CNS). Besides MMPSI, SLACK GOF mutations have also been associated with other forms of epilepsy, including Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, and others.

What is quite counterintuitive here is that SLACK GOF mutations lead to increased neuronal excitability, despite the fact that potassium channel opening is usually associated with a decrease in neuronal excitability. Two proposed potential mechanisms for this are: 1) SLACK GOF mutations decrease the activity of GABAergic inhibitory interneurons, resulting in an excitatory/inhibitory imbalance; 2) SLACK GOF mutations increase the amplitude of the afterhyperpolarization that follows each action potential, thereby increasing the neuronal firing rate.

Overall, existing data suggests that the SLACK channel is a prime target for therapeutic intervention in KCNT1-associated epilepsies. Nevertheless, until now, there has been a lack of high-quality tool compounds that selectively inhibit SLACK channels.

In a recent study, researchers performed a high-throughput screening campaign that led to the identification of VU0531245 (VU245) as a promising SLACK channel inhibitor. Following this, a series of structure-activity relationship (SAR) studies were conducted, leading to the creation of various VU245 analogs. These analogs were rigorously tested for their metabolic stability, plasma-protein binding, and selectivity. The SLACK inhibitory activity of the analogs was assessed in whole-cell, voltage-clamp electrophysiology assays utilizing an automated patch clamp system, the SyncroPatch 384. These experiments revealed submicromolar potency for multiple analogs, including VU0935685, an analog showing improved inhibitory activity against SLACK channels, alongside better selectivity for related potassium channels and modest improvements in metabolic clearance.

Overall, this study identified VU0935685 as a novel and structurally distinct SLACK inhibitor, which provides a valuable in vitro tool for further exploration into SLACK channels’ role in epilepsy.


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Learn more about the SyncroPatch 384, an automated patch clamp instrument with 384 recording channels incorporated into a state-of-art liquid handling robot.