2. Academic Validation
  3. Design, synthesis, and biological evaluation of a novel series of 1,2,4-oxadiazole inhibitors of SLACK potassium channels: Identification of in vitro tool VU0935685

Design, synthesis, and biological evaluation of a novel series of 1,2,4-oxadiazole inhibitors of SLACK potassium channels: Identification of in vitro tool VU0935685

  • Bioorg Med Chem. 2023 Sep 30:95:117487. doi: 10.1016/j.bmc.2023.117487.
Alshaima'a M Qunies 1,  Brittany D Spitznagel 2,  Yu Du 3,  C David Weaver 3,  Kyle A Emmitte 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
  • 2 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
  • 3 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
  • 4 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. Electronic address: [email protected].
PMID: 37812884 DOI: 10.1016/j.bmc.2023.117487
Abstract

Malignant migrating partial seizure of infancy (MMPSI) is a devastating and pharmacoresistant form of infantile epilepsy. MMPSI has been linked to multiple gain-of-function (GOF) mutations in the KCNT1 gene, which encodes for a Potassium Channel often referred to as SLACK. SLACK channels are sodium-activated potassium channels distributed throughout the central nervous system (CNS) and the periphery. The investigation described here aims to discover SLACK channel inhibitor tool compounds and profile their pharmacokinetic and pharmacodynamic properties. A SLACK channel inhibitor VU0531245 (VU245) was identified via a high-throughput screen (HTS) campaign. Structure-activity relationship (SAR) studies were conducted in five distinct regions of the hit VU245. VU245 analogs were evaluated for their ability to affect SLACK channel activity using a thallium flux assay in HEK-293 cells stably expressing wild-type (WT) human SLACK. Selected analogs were tested for metabolic stability in mouse liver microsomes and plasma-protein binding in mouse plasma. The same set of analogs was tested via thallium flux for activity versus human A934T SLACK and other structurally related potassium channels, including SLICK and Maxi-K. In addition, potencies for selected VU245 analogs were obtained using whole-cell electrophysiology (EP) assays in CHO cells stably expressing WT human SLACK through an automated patch clamp system. Results revealed that this scaffold tolerates structural changes in some regions, with some analogs demonstrating improved SLACK inhibitory activity, good selectivity against the other channels tested, and modest improvements in metabolic clearance. Analog VU0935685 represents a new, structurally distinct small-molecule inhibitor of SLACK channels that can serve as an in vitro tool for studying this target.

Keywords

1,2,4-oxadiazoles; EIMFS; K(Na)1.1; KCNT1; MMPSI; Slack; Slo2.2.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156335
    SLACK Channel Inhibitor