Pharmaceutical Sciences Faculty Publications

Title

Development of a Selective Chemical Inhibitor for the Two-Pore Potassium Channel, KCNK9

Document Type

Web Publication

Publication Date

2013

PubMed ID

23658958

Abstract

ML308 was identified as a novel inhibitor of the potassium channel, subfamily K, member 9 (KCNK9) two-pore domain potassium channel. Two-pore domain potassium channels provide a background leak conductance that is selectively permeable to potassium. These channels regulate cell membrane potential and excitability and thereby modulate a variety of processes including hormone secretion, proliferation, and central nervous system (CNS) function. A high throughput fluorescent screen measuring thallium influx through KCNK9 channels was used to identify bisamide and thiotriazole classes of inhibitors. Chemical modification of the thiotriazole scaffold yielded ML308 which displayed a potent block of KCNK9 channels in a thallium influx fluorescent assay (IC50 = 130 nM) and in an automated electrophysiology assay (IC50 = 413 nM). ML308 afforded >50-fold selectivity for block of KCNK9 over the closely-related, two-pore domain potassium channel, KCNK3, in fluorescent assays and displayed little or no block at 10 μM of the more distantly related potassium channels, Kir2.1, potassium voltage-gated channel, KQT-like subfamily, member 2 (KCNQ2), and human ether-a go-go-related gene (HERG). The potency and selectivity profile of ML308 makes it a useful pharmacological probe for in vitro studies of KCNK9 function and in further studies aimed at therapeutic intervention.

Keywords

Chemicals, inhibitors, potassium channels, KCNK9

Comments

In Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information, 2013.