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

Bjoern Bielec,Bernhard K Keppler,Esra Ahmed,Isabella Poetsch,Petra Heffeter,Christian R Kowol

doi:10.3390/molecules25051149

Bjoern Bielec, Bernhard K Keppler + Show 4 more

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https://doi.org/10.3390/molecules25051149

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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) cell line.

Highlights

Tyrosine kinases catalyze the transfer of the γ-phosphate groups of adenosine triphosphate (ATP) between enzymes and play a central role in cell signaling pathways from the cell surface to the nucleus [1]
The class of tyrosine kinase inhibitors (TKIs) consists of small-molecule anticancer therapeutics competing with ATP in the active sites of tyrosine kinases, most frequently in a reversible and competitive manner [3]
In order to verify the reduced ability to enter and form strong bonds with the ATP-binding pockets of ALK and c-MET, the ligand-binding modes of both prodrugs were compared with crizotinib via molecular docking studies

Summary

Introduction

Tyrosine kinases catalyze the transfer of the γ-phosphate groups of adenosine triphosphate (ATP) between enzymes and play a central role in cell signaling pathways from the cell surface to the nucleus [1] They are involved in cellular processes like differentiation, proliferation, and apoptosis. In cancer cells, these proteins are frequently activated in an aberrant manner that can lead to tumor formation or metastasis [2]. These proteins are frequently activated in an aberrant manner that can lead to tumor formation or metastasis [2] Inhibition of these enzymes is a successful strategy in anticancer therapy and has led to the approval of several different classes of targeted therapeutics [3,4]. The efficacy of an inhibitor is determined by its dissociation constant that relies on the chemical structure of the drug

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