Selective TASK-1 Inhibitor with a Defined Structure-Activity Relationship Reduces Cancer Cell Proliferation and Viability

Bárbara Arévalo, Mauricio Bedoya, Aytug K. Kiper, Fernando Vergara, David Ramírez, Yuliet Mazola, Daniel Bustos, Rafael Zúñiga, Rocio Cikutovic, Angel Cayo, Susanne Rinné, M. Teresa Ramirez-Apan, Francisco V. Sepúlveda, Oscar Cerda, Eduardo López-Collazo, Niels Decher*, Leandro Zúñiga*, Margarita Gutierrez*, Wendy González*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Chemical structures of selective blockers of TASK channels contain aromatic groups and amide bonds. Using this rationale, we designed and synthesized a series of compounds based on 3-benzamidobenzoic acid. These compounds block TASK-1 channels by binding to the central cavity. The most active compound is 3-benzoylamino-N-(2-ethyl-phenyl)-benzamide or F3, blocking TASK-1 with an IC50 of 148 nM, showing a reduced inhibition of TASK-3 channels and not a significant effect on different K+ channels. We identified putative F3-binding sites in the TASK-1 channel by molecular modeling studies. Mutation of seven residues to A (I118A, L122A, F125A, Q126A, L232A, I235A, and L239A) markedly decreased the F3-induced inhibition of TASK-1 channels, consistent with the molecular modeling predictions. F3 blocks cell proliferation and viability in the MCF-7 cancer cell line but not in TASK-1 knockdown MCF-7 cells, indicating that it is acting in TASK-1 channels. These results indicated that TASK-1 is necessary to drive proliferation in the MCF-7 cancer cell line.

Original languageEnglish
Pages (from-to)15014-15027
Number of pages14
JournalJournal of Medicinal Chemistry
Volume65
Issue number22
DOIs
StatePublished - 2022

Bibliographical note

Publisher Copyright:
© 2022 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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