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Isothermal kinase-triggered supramolecular assemblies as drug sensitizers

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Abstract

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.

Graphical abstract: Isothermal kinase-triggered supramolecular assemblies as drug sensitizers

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Supplementary files

Article information


Submitted
27 Aug 2019
Accepted
05 Dec 2019
First published
06 Dec 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Isothermal kinase-triggered supramolecular assemblies as drug sensitizers

D. Liu, Z. Miao, C. Wu, F. He, P. Ren, S. Bai, X. Jiang and Y. Gao, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC04317A

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