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1.
ChemMedChem ; 13(22): 2415-2426, 2018 11 20.
Article in English | MEDLINE | ID: mdl-30199151

ABSTRACT

The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this context, the tyrosine kinase inhibitor axitinib, which contains a photosensitive stilbene-like moiety that allows for E/Z isomerization, is of interest. Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. The photoinduced E/Z isomerization of axitinib has been investigated to explore if its inhibitory effect can be turned "on" and "off", as triggered by light. Under controlled light conditions, (Z)-axitinib is 43 times less active than that of the E isomer in an VEGFR2 assay. Furthermore, it was proven that kinase activity in human umbilical vein cells (HUVECs) was decreased by (E)-axitinib, but only weakly affected by (Z)-axitinib. By irradiating (Z)-axitinib in vitro with UV light (λ=385 nm), it is possible to switch it almost quantitatively into the E isomer and to completely restore the biological activity of (E)-axitinib. However, switching the biological activity off from (E)- to (Z)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition, which yielded a biologically inactive axitinib dimer.


Subject(s)
Axitinib/chemistry , Axitinib/radiation effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/radiation effects , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Axitinib/chemical synthesis , Binding Sites , Dose-Response Relationship, Drug , Enzyme Assays , Human Umbilical Vein Endothelial Cells , Humans , Isomerism , Mice , Molecular Docking Simulation , NIH 3T3 Cells , Protein Kinase Inhibitors/chemical synthesis , Ultraviolet Rays , Vascular Endothelial Growth Factor Receptor-2/chemistry
2.
Molecules ; 21(5)2016 Apr 29.
Article in English | MEDLINE | ID: mdl-27136525

ABSTRACT

In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.


Subject(s)
Prodrugs , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Cell Line , Cell Proliferation/drug effects , Drug Design , Molecular Structure , Photochemical Processes , Prodrugs/radiation effects , Ultraviolet Rays , Vascular Endothelial Growth Factor Receptor-2/administration & dosage
3.
ChemMedChem ; 10(8): 1335-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26076342

ABSTRACT

Imatinib is the first protein kinase inhibitor approved for clinical use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymatic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by ultraviolet light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacological tool to study the impact of imatinib toward biological systems in greater detail.


Subject(s)
Drug Design , Imatinib Mesylate/chemistry , Prodrugs/chemistry , Protein Kinase Inhibitors/chemical synthesis , Binding Sites , Catalytic Domain , Imatinib Mesylate/chemical synthesis , Molecular Docking Simulation , Prodrugs/chemical synthesis , Protein Kinase Inhibitors/chemistry , Receptor, Platelet-Derived Growth Factor beta/chemistry , Receptor, Platelet-Derived Growth Factor beta/metabolism , Ultraviolet Rays
4.
ACS Chem Biol ; 10(9): 2099-107, 2015 Sep 18.
Article in English | MEDLINE | ID: mdl-26061392

ABSTRACT

In this study, we report on novel photoactivatable caged prodrugs of vemurafenib. This kinase inhibitor was the first approved drug for the personalized treatment of BRAF-mutated melanoma and showed impressive results in clinical studies. However, the occurrence of severe side effects and drug resistance illustrates the urgent need for innovative therapeutic approaches. To conquer these limitations, we implemented photoremovable protecting groups into vemurafenib. In general, this caging concept provides spatial and temporal control over the activation of molecules triggered by ultraviolet light. Thus, higher inhibitor concentrations in tumor tissues might be reached with less systemic effects. Our study describes the first development of caged vemurafenib prodrugs useful as pharmacological tools. We investigated their photochemical characteristics and photoactivation. In vitro evaluation proved the intended loss-of-function and the light-dependent recovery of efficacy in kinase and cellular assays. The reported vemurafenib photo prodrugs represent a powerful biological tool for novel pharmacological approaches in cancer research.


Subject(s)
Indoles/chemistry , Indoles/pharmacology , Melanoma/drug therapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Humans , Melanoma/genetics , Melanoma/pathology , Models, Molecular , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Vemurafenib
5.
J Med Chem ; 58(1): 170-82, 2015 Jan 08.
Article in English | MEDLINE | ID: mdl-25007344

ABSTRACT

In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) ß-inhibitors. Originally, the 3,5-diaryl-pyrazin-2-one core was derived from the marine sponge alkaloid family of hamacanthins. In our first series compound 2 was discovered as a promising hit showing strong activity against PDGF-Rß in the kinase assay (IC50 = 0.5 µM). Furthermore, 2 was shown to be selective for PDGF-Rß in a panel of 24 therapeutically relevant protein kinases. Molecular modeling studies on a PDGF-Rß homology model using prediction of water thermodynamics suggested an optimization strategy for the 3,5-diaryl-pyrazin-2-ones as DFG-in binders by using a phenolic OH function to replace a structural water molecule in the ATP binding site. Indeed, we identified compound 38 as a highly potent inhibitor with an IC50 value of 0.02 µM in a PDGF-Rß enzymatic assay also showing activity against PDGF-R dependent cancer cells.


Subject(s)
Protein Kinase Inhibitors/chemistry , Receptor, Platelet-Derived Growth Factor beta/chemistry , Small Molecule Libraries/chemistry , Thermodynamics , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Binding, Competitive , Humans , Models, Chemical , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrazines/chemistry , Pyrazines/metabolism , Pyrazines/pharmacology , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/metabolism , Signal Transduction/drug effects , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Water/chemistry
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