Comparison of the Kinase Profile of Midostaurin (Rydapt) with That of Its Predominant Metabolites and the Potential Relevance of Some Newly Identified Targets to Leukemia Therapy
| العنوان: | Comparison of the Kinase Profile of Midostaurin (Rydapt) with That of Its Predominant Metabolites and the Potential Relevance of Some Newly Identified Targets to Leukemia Therapy |
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| المؤلفون: | Johannes Roesel, Giorgio Caravatti, Trixie Wagner, Pascal Furet, Markus Wartmann, Paul W. Manley, Phi Tran |
| المصدر: | Biochemistry. 57:5576-5590 |
| بيانات النشر: | American Chemical Society (ACS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, BALB 3T3 Cells, medicine.drug_class, Newly diagnosed, Biochemistry, Gene Expression Regulation, Enzymologic, Mice, 03 medical and health sciences, chemistry.chemical_compound, hemic and lymphatic diseases, medicine, Animals, Humans, Midostaurin, Systemic mastocytosis, Protein Kinase Inhibitors, Cells, Cultured, Cell Proliferation, Kinase, business.industry, Gene Expression Profiling, Myeloid leukemia, Fibroblasts, Protein kinase inhibitor, Staurosporine, medicine.disease, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, fms-Like Tyrosine Kinase 3, chemistry, Mutation, Cancer research, business |
| الوصف: | The multitargeted protein kinase inhibitor midostaurin is approved for the treatment of both newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and KIT-driven advanced systemic mastocytosis. AML is a heterogeneous malignancy, and investigational drugs targeting FLT3 have shown disparate effects in patients with FLT3-mutated AML, probably as a result of their inhibiting different targets and pathways at the administered doses. However, the efficacy and side effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound but are often comprised of complex cooperative effects between the properties of the parent and active metabolites. Following chronic dosing, two midostaurin metabolites attain steady-state plasma trough levels greater than that of the parent drug. In this study, we characterized these metabolites and determined their profiles as kinase inhibitors using radiometric transphosphorylation assays. Like midostaurin, the metabolites potently inhibit mutant forms of FLT3 and KIT and several additional kinases that either are directly involved in the deregulated signaling pathways or have been implicated as playing a role in AML via stromal support, such as IGF1R, LYN, PDPK1, RET, SYK, TRKA, and VEGFR2. Consequently, a complex interplay between the kinase activities of midostaurin and its metabolites is likely to contribute to the efficacy of midostaurin in AML and helps to engender the distinctive effects of the drug compared to those of other FLT3 inhibitors in this malignancy. |
| تدمد: | 1520-4995 0006-2960 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0942e87419d9a46e47e02e694a107120 https://doi.org/10.1021/acs.biochem.8b00727 |
| رقم الأكسشن: | edsair.doi.dedup.....0942e87419d9a46e47e02e694a107120 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204995 00062960 |
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