Discovery of Potent and Selective Blockers Targeting the Epilepsy-Associated KNa1.1 Channel

Gain-of-function (GOF) mutations of the sodium-activated potassium channel K_Na1.1 (Slack, Slo2.2, or K_Ca4.1) induce severe, drug-resistant forms of epilepsy in infants and children. Although quinidine has shown promise in treating KCNT1-related epilepsies compared to other drugs, its limited efficacy and substantial side effects necessitate the development of new K_Na1.1 channel inhibitors. In this study, we developed a novel class of K_Na1.1 inhibitors using combined silico approaches and structural optimization. Among these inhibitors, compound Z05 was identified as a selective potential K_Na1.1 inhibitor, especially against the hERG channel. Moreover, its binding site and potential counteraction to a GOF mutant Y796H were identified by the mutation studies. Our data also showed that Z05 had significant pharmacological profiles, including high brain penetration and moderate oral bioavailability, offering a valuable in vitro tool compound for further drug development in treating KCNT1-related epilepsies.