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Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators

In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC(50)=2.25...

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Autores principales: Liu, Yilin, Song, Yuming, Xu, Yingju, Jiang, Meixu, Lu, Haibin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225785/
https://www.ncbi.nlm.nih.gov/pubmed/35698881
http://dx.doi.org/10.1080/14756366.2022.2087219
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author Liu, Yilin
Song, Yuming
Xu, Yingju
Jiang, Meixu
Lu, Haibin
author_facet Liu, Yilin
Song, Yuming
Xu, Yingju
Jiang, Meixu
Lu, Haibin
author_sort Liu, Yilin
collection PubMed
description In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC(50)=2.25 µM) and U239 (IC(50)=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC(50)=0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC(50)=4.83 µM), and the docking study confirmed a nice fitting of 10a into the active sites of CRBN. Further biology studies revealed compound 10a can increase the apoptotic events, arrest the NCI-H929 cells at G0/G1 cell cycle, and induce the ubiquitination degradation of IKZF1 and IKZF3 proteins by CRL4(CRBN). These preliminary results suggested that compound 10a could serve as a potential antitumor drug and worthy of further investigation.
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spelling pubmed-92257852022-06-24 Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators Liu, Yilin Song, Yuming Xu, Yingju Jiang, Meixu Lu, Haibin J Enzyme Inhib Med Chem Research Paper In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC(50)=2.25 µM) and U239 (IC(50)=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC(50)=0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC(50)=4.83 µM), and the docking study confirmed a nice fitting of 10a into the active sites of CRBN. Further biology studies revealed compound 10a can increase the apoptotic events, arrest the NCI-H929 cells at G0/G1 cell cycle, and induce the ubiquitination degradation of IKZF1 and IKZF3 proteins by CRL4(CRBN). These preliminary results suggested that compound 10a could serve as a potential antitumor drug and worthy of further investigation. Taylor & Francis 2022-06-14 /pmc/articles/PMC9225785/ /pubmed/35698881 http://dx.doi.org/10.1080/14756366.2022.2087219 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Liu, Yilin
Song, Yuming
Xu, Yingju
Jiang, Meixu
Lu, Haibin
Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators
title Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators
title_full Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators
title_fullStr Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators
title_full_unstemmed Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators
title_short Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators
title_sort design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2h,4h)-dione derivatives as cereblon modulators
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225785/
https://www.ncbi.nlm.nih.gov/pubmed/35698881
http://dx.doi.org/10.1080/14756366.2022.2087219
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