TY - JOUR
T1 - Selective TASK-1 Inhibitor with a Defined Structure-Activity Relationship Reduces Cancer Cell Proliferation and Viability
AU - Arévalo, Bárbara
AU - Bedoya, Mauricio
AU - Kiper, Aytug K.
AU - Vergara, Fernando
AU - Ramírez, David
AU - Mazola, Yuliet
AU - Bustos, Daniel
AU - Zúñiga, Rafael
AU - Cikutovic, Rocio
AU - Cayo, Angel
AU - Rinné, Susanne
AU - Ramirez-Apan, M. Teresa
AU - Sepúlveda, Francisco V.
AU - Cerda, Oscar
AU - López-Collazo, Eduardo
AU - Decher, Niels
AU - Zúñiga, Leandro
AU - Gutierrez, Margarita
AU - González, Wendy
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/11/24
Y1 - 2022/11/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141962460&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00378
DO - 10.1021/acs.jmedchem.1c00378
M3 - Article
C2 - 36378530
AN - SCOPUS:85141962460
SN - 0022-2623
VL - 65
SP - 15014
EP - 15027
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -