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

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<i>-N</i>-(2-ethyl-phenyl)-benzamide or <b>F3</b>, 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. <b>F3</b> 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.