VU0948578: a new xanthine-based inhibitor of KCNT1 channels

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, severe epileptic disorder characterized by early onset seizures resistant to standard treatments. EIMFS is associated with mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel SLACK (KNa1.1, Slo2.2).

SLACK channels regulate neural excitability, playing a key role in afterhyperpolarization (AHP) following neural discharges. Gain-of-function (GOF) mutations in KCNT1 increase SLACK activity, contributing to heightened neuronal excitability and seizures.

Given the pivotal role of SLACK channels in EIMFS, they represent a prime target for therapeutic intervention. However, the development of selective SLACK channel inhibitors has been challenging, with older non-selective inhibitors such as quinidine showing limited efficacy and significant toxicity.

In a recent study, researchers embarked on a high-throughput screening campaign, identifying the xanthine-based compound VU0607689 as a promising SLACK channel inhibitor. Following this discovery, the team conducted extensive structure-activity relationship (SAR) studies, synthesizing 58 new analogs and evaluating them for SLACK inhibitory activity.

Using whole-cell automated patch-clamp electrophysiology assay (the SyncroPatch 768 PE), the researchers tested these analogs on wild-type (WT) and clinically relevant SLACK mutants (A934T and G288S). Several analogs demonstrated submicromolar potency, with compound VU0948578 emerging as particularly noteworthy. This compound exhibited IC50 values between 0.59 and 0.71 µM across WT and mutant SLACK channels, highlighting its potential as a valuable in vitro tool compound.

The study also assessed the selectivity of these analogs against a variety of other ion channels, including hERG. The results were promising, showing good selectivity and minimal off-target effects, which is crucial for developing safe and effective therapies.

In summary, this research has successfully identified VU0948578 as a novel and structurally distinct SLACK inhibitor. This compound not only offers a potent tool for further investigating SLACK channels’ role in epilepsy but also paves the way for developing new therapeutic strategies for EIMFS and related neurological disorders. The next steps will involve evaluating the metabolic and physicochemical properties of these inhibitors to ensure their suitability for in vivo studies and potential clinical applications.

Find the full article here: https://www.mdpi.com/1420-3049/29/11/2437

Learn more about the SyncroPatch 384, an automated patch clamp instrument with 384 recording channels incorporated into a state-of-art liquid handling robot: https://www.nanion.de/products/syncropatch-384/