2. Academic Validation
  3. In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel

  • J Med Chem. 2024 Jun 13;67(11):9124-9149. doi: 10.1021/acs.jmedchem.4c00268.
Nunzio Iraci 1,  Lidia Carotenuto 2,  Tania Ciaglia 3,  Giorgio Belperio 4,  Francesca Di Matteo 3,  Ilaria Mosca 5,  Giusy Carleo 2,  Manuela Giovanna Basilicata 6,  Paolo Ambrosino 4,  Rita Turcio 3,  Deborah Puzo 5,  Giacomo Pepe 3,  Isabel Gomez-Monterrey 7,  Maria Virginia Soldovieri 5,  Veronica Di Sarno 3,  Pietro Campiglia 3,  Francesco Miceli 2,  Alessia Bertamino 3,  Carmine Ostacolo 3,  Maurizio Taglialatela 2
Affiliations

Affiliations

  • 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences (CHIBIOFARAM), University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
  • 2 Department of Neuroscience, Reproductive Sciences and Dentistry, University Federico II of Naples, Via S. Pansini, 5, 80131 Naples, Italy.
  • 3 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084 Fisciano, SA, Italy.
  • 4 Department of Science and Technology, University of Sannio, Via F. De Sanctis, 82100 Benevento, Italy.
  • 5 Department of Medicine and Health Science Vincenzo Tiberio, University of Molise, Via C. Gazzani, 86100 Campobasso, Italy.
  • 6 Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia 2, 80138 Naples, Italy.
  • 7 Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131 Naples, Italy.
PMID: 38782404 DOI: 10.1021/acs.jmedchem.4c00268
Abstract

Gain-of-function (GoF) variants in KCNT1 channels cause severe, drug-resistant forms of epilepsy. Quinidine is a known KCNT1 blocker, but its clinical use is limited due to severe drawbacks. To identify novel KCNT1 blockers, a homology model of human KCNT1 was built and used to screen an in-house library of compounds. Among the 20 molecules selected, five (CPK4, 13, 16, 18, and 20) showed strong KCNT1-blocking ability in an in vitro fluorescence-based assay. Patch-clamp experiments confirmed a higher KCNT1-blocking potency of these compounds when compared to quinidine, and their selectivity for KCNT1 over hERG and Kv7.2 channels. Among identified molecules, CPK20 displayed the highest metabolic stability; this compound also blocked KCNT2 currents, although with a lower potency, and counteracted GoF effects prompted by 2 recurrent epilepsy-causing KCNT1 variants (G288S and A934T). The present results provide solid rational basis for future design of novel compounds to counteract KCNT1-related neurological disorders.

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