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Selective TASK-1 inhibitor with a defined structure–activity relationship reduces cancer cell proliferation and viability

dc.contributor.authorArévalo, Bárbara
dc.contributor.authorBedoya, Mauricio
dc.contributor.authorKiper, Aytug K.
dc.contributor.authorVergara, Fernando
dc.contributor.authorRamírez, David
dc.contributor.authorMazola, Yuliet
dc.contributor.authorBustos, Daniel
dc.contributor.authorZúñiga, Rafael
dc.contributor.authorCikutovic, Rocio
dc.contributor.authorCayo, Angel
dc.contributor.authorRinné, Susanne
dc.contributor.authorRamirez-Apan, M. Teresa
dc.contributor.authorSepúlveda, Francisco V.
dc.contributor.authorCerda, Oscar
dc.contributor.authorLópez-Collazo, Eduardo
dc.contributor.authorDecher, Niels
dc.contributor.authorZúñiga, Leandro
dc.contributor.authorGutiérrez, Margarita
dc.contributor.authorGonzález, Wendy
dc.date.accessioned2023-01-04T19:16:31Z
dc.date.available2023-01-04T19:16:31Z
dc.date.issued2021
dc.identifier.urihttp://repositorio.ucm.cl/handle/ucm/4341
dc.description.abstractChemical 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.es_CL
dc.language.isoenes_CL
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
dc.sourceJournal of Medicinal Chemistry, 65(22), 15014-15027es_CL
dc.titleSelective TASK-1 inhibitor with a defined structure–activity relationship reduces cancer cell proliferation and viabilityes_CL
dc.typeArticlees_CL
dc.ucm.facultadFacultad de Medicinaes_CL
dc.ucm.indexacionScopuses_CL
dc.ucm.indexacionIsies_CL
dc.ucm.uripubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c00378es_CL
dc.ucm.doidoi.org/10.1021/acs.jmedchem.1c00378es_CL


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Atribución-NoComercial-SinDerivadas 3.0 Chile
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