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

  • J Med Chem. 2024 Nov 14;67(21):19519-19545. doi: 10.1021/acs.jmedchem.4c01815.
Ruqiu Zheng  1 ,  Zhongtang Li  1  2 ,  Qiufeng Wang  1 ,  Shiqi Liu  1 ,  Ningfeng Liu  1 ,  Yiyan Li  1 ,  Guiwang Zhu  1 ,  Zhenming Liu  1 ,  Zhuo Huang  1  2 ,  Liangren Zhang  1
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 2. Ningbo Institute of Marine Medicine, Peking University, Ningbo 315832, China.
PMID: 39445572 DOI: 10.1021/acs.jmedchem.4c01815
Abstract

Gain-of-function (GOF) mutations of the sodium-activated Potassium Channel KNa1.1 (Slack, Slo2.2, or KCA4.1) 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 KNa1.1 channel inhibitors. In this study, we developed a novel class of KNa1.1 inhibitors using combined silico approaches and structural optimization. Among these inhibitors, compound Z05 was identified as a selective potential KNa1.1 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.

Products