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Isothermal kinase-triggered supramolecular assemblies as drug sensitizers

Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails ev...

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Detalles Bibliográficos
Autores principales: Liu, Dongdong, Miao, Zhe, Wu, Chengling, He, Fangfei, Ren, Peng, Bai, Shuo, Jiang, Xingyu, Gao, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145944/
https://www.ncbi.nlm.nih.gov/pubmed/34084370
http://dx.doi.org/10.1039/c9sc04317a
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author Liu, Dongdong
Miao, Zhe
Wu, Chengling
He, Fangfei
Ren, Peng
Bai, Shuo
Jiang, Xingyu
Gao, Yuan
author_facet Liu, Dongdong
Miao, Zhe
Wu, Chengling
He, Fangfei
Ren, Peng
Bai, Shuo
Jiang, Xingyu
Gao, Yuan
author_sort Liu, Dongdong
collection PubMed
description Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails even in animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the cytoskeleton and sensitizes cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated cancer.
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spelling pubmed-81459442021-06-02 Isothermal kinase-triggered supramolecular assemblies as drug sensitizers Liu, Dongdong Miao, Zhe Wu, Chengling He, Fangfei Ren, Peng Bai, Shuo Jiang, Xingyu Gao, Yuan Chem Sci Chemistry Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails even in animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the cytoskeleton and sensitizes cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated cancer. The Royal Society of Chemistry 2019-12-06 /pmc/articles/PMC8145944/ /pubmed/34084370 http://dx.doi.org/10.1039/c9sc04317a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Liu, Dongdong
Miao, Zhe
Wu, Chengling
He, Fangfei
Ren, Peng
Bai, Shuo
Jiang, Xingyu
Gao, Yuan
Isothermal kinase-triggered supramolecular assemblies as drug sensitizers
title Isothermal kinase-triggered supramolecular assemblies as drug sensitizers
title_full Isothermal kinase-triggered supramolecular assemblies as drug sensitizers
title_fullStr Isothermal kinase-triggered supramolecular assemblies as drug sensitizers
title_full_unstemmed Isothermal kinase-triggered supramolecular assemblies as drug sensitizers
title_short Isothermal kinase-triggered supramolecular assemblies as drug sensitizers
title_sort isothermal kinase-triggered supramolecular assemblies as drug sensitizers
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145944/
https://www.ncbi.nlm.nih.gov/pubmed/34084370
http://dx.doi.org/10.1039/c9sc04317a
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