Reactive Oxygen Species (ROS)-Sensitive Prodrugs of the Tyrosine Kinase Inhibitor Crizotinib.

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Bjoern BielecChristian R Kowol

Abstract

Tyrosine kinase inhibitors revolutionized cancer therapy but still evoke strong adverse effects that can dramatically reduce patients' quality of life. One possibility to enhance drug safety is the exploitation of prodrug strategies to selectively activate a drug inside the tumor tissue. In this study, we designed a prodrug strategy for the approved c-MET, ALK, and ROS1 tyrosine kinase inhibitor crizotinib. Therefore, a boronic-acid trigger moiety was attached to the 2-aminopyridine group of crizotinib, which is a crucial position for target kinase binding. The influence of the modifications on the c-MET- and ALK-binding ability was investigated by docking studies, and the strongly reduced interactions could be confirmed by cell-free kinase inhibition assay. Furthermore, the newly synthesized compounds were tested for their activation behavior with H2O2 and their stability in cell culture medium and serum. Finally, the biological activity of the prodrugs was investigated in three cancer cell lines and revealed a good correlation between activity and intrinsic H2O2 levels of the cells for prodrug A. Furthermore, the activity of this prodrug was distinctly reduced in a non-malignant, c-MET expressing human lung fibroblast (HLF) c...Continue Reading

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Citations

Sep 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mariana Pereira SilvaMaria Emília Sousa
Aug 29, 2020·European Journal of Medicinal Chemistry·Hichem MaslahRaphaël Labruère
Oct 13, 2021·Chembiochem : a European Journal of Chemical Biology·Eron Saxon, Xiaohua Peng

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Methods Mentioned

BETA
chemical modification
column chromatography
FCS
flow cytometry
NMR
Assay

Software Mentioned

AutoDock Vina
SwissADME
ChemBioDraw ® Office Suite
GraphPad Prism
ChemBio3D
AutoDockTools
ChemStation
PyMol
Gaussian09
LigPlot +

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