Frontiers in Pharmacology (Jun 2025)

KU124 (9,10,10-trioxo-N-(2-phenylphenyl)thioxanthene-3-carboxamide) as a novel inhibitor of TASK-1

  • Ana Dumani,
  • Annette Jacob,
  • Diego Chavez,
  • Abena Amankwaa,
  • Ramish Zahed,
  • Martha Julemis,
  • Hinaben Patel,
  • Joana Lopez,
  • Steven Almazan,
  • Patrick Martins,
  • Anthony Contreras,
  • Sofiia Korotka,
  • Gianna Kiszka,
  • Alexander Aleynik,
  • Justin Patino,
  • David Graham,
  • Megan Blaisdell,
  • Youssef Elhowary,
  • Shuayb Yousuf,
  • Chelsea Pelley,
  • Jenna Marciano,
  • Jessica Best,
  • Rhustie Valdizno,
  • Nikki Mastrodomenico,
  • Jonelle Brown,
  • Sarah Schwartz,
  • Irene Anin,
  • Yara Farrag,
  • Rinchu George,
  • Gianna Medeiros,
  • Sophia Lang,
  • Marilyn Dennis,
  • Oluwatoni Awoleye,
  • Lamont Lee,
  • Ericka Salgado,
  • Diana Figueroa Chea,
  • Thomas Walter Comollo,
  • Thomas Walter Comollo

DOI
https://doi.org/10.3389/fphar.2025.1577171
Journal volume & issue
Vol. 16

Abstract

Read online

TASK-1 is a two-pore K+ leak channel. The name, TASK-1, stands for TWIK-related acid-sensitive potassium channel 1, and this channel is encoded by the KCNK3 gene. TASK-1 channels are expressed in humans and modulate cell excitability in excitable cells such as neurons, cardiomyocytes, and vascular smooth muscle cells. TASK-1 inhibition is a mechanism of action for some respiratory stimulants, such as doxapram. TASK-1 channels have also been suggested to play a role in circumventing cell apoptosis in a population of non-small-cell lung cancer cells. We propose that the inner vestibule of the TASK-1 channel, a known binding site of known TASK-1 inhibitors, BAY10000493 and BAY2341237, can be exploited via virtual screening to find other novel TASK-1 inhibitors. Our results show that by targeting the inner vestibule site, we found an active TASK-1 inhibitor. We suspect that this region of interest can be further exploited to discover additional TASK-1 inhibitors. Our initial success lends validity to our virtual screening methodology and parameters. In this study, we identified a novel TASK-1 inhibitor, KU124, which we verified using an in vitro assay.

Keywords