Reactive Oxygen Species (ROS)-Sensitive Prodrugs of the Tyrosine Kinase Inhibitor Crizotinib.
Bjoern BielecIsabella PoetschEsra AhmedPetra HeffeterBernhard K KepplerChristian R KowolPublished in: Molecules (Basel, Switzerland) (2020)
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) cell line.
Keyphrases
- cancer therapy
- advanced non small cell lung cancer
- reactive oxygen species
- tyrosine kinase
- cell free
- drug delivery
- epidermal growth factor receptor
- end stage renal disease
- drug release
- cell death
- chronic kidney disease
- newly diagnosed
- ejection fraction
- dna damage
- induced apoptosis
- cell cycle arrest
- atomic force microscopy
- prognostic factors
- molecular dynamics
- protein kinase
- squamous cell carcinoma
- high throughput
- binding protein
- dna binding
- mass spectrometry
- case control
- patient reported outcomes
- pi k akt