ML365: Development of Bis-Amides as Selective Inhibitors of the KCNK3/TASK1 Two Pore Potassium Channel
Two-pore domain potassium channels play important roles in regulation of cell membrane potential. Their activities modulate a variety of physiological processes including immune response, hormone secretion, chemosensation, and neuronal function. ML365 was identified as a novel selective small molecule inhibitor of the TASK1 or potassium channel, subfamily K, member 9 (KCNK3) two-pore domain potassium channel following a high throughput fluorescent screen of the Molecular Libraries Small Molecule Repository (MLSMR) library and structure activity relationship (SAR) analysis of active compounds. The fluorescent screen measuring thallium influx through TASK1 channels was used to identify the bisamide class of inhibitors. Chemical modification yielded a potent and selective inhibitor, ML365. The compound blocks TASK1 channels in both the thallium influx fluorescent assay (IC50 = 4 nM) and an automated electrophysiology assay (IC50 = 16 nM). Based on potency differences, it possesses more than 60-fold selectivity for inhibition of TASK1 over a closely-related, two-pore domain potassium channel, TASK3. ML365 displays little or no inhibition at 30 μM of 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). Based on these criteria, ML365 is a best-in-class probe and is a useful pharmacological probe for in vitro studies of TASK1 function and in further studies aimed at developing therapeutic intervention.
Cell membranes, potassium channels, ML365, inhibitors
Zou, Beiyan; Flaherty, Daniel P.; Simpson, Denise S.; Maki, Brooks E.; Miller, Melissa R.; Shi, Jie; Wu, Meng; McManus, Owen B.; Golden, Jennifer E.; Aubé, Jeffrey; and Li, Min, "ML365: Development of Bis-Amides as Selective Inhibitors of the KCNK3/TASK1 Two Pore Potassium Channel" (2013). Pharmaceutical Sciences Faculty Publications. 157.