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.

Abstract

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.

• Authors: Paul W Manley, Giorgio Caravatti, Pascal Furet, Johannes Roesel, Phi Tran, Trixie Wagner, Markus Wartmann
• Journal: Biochemistry (Biochemistry) Vol. 57 Issue 38 Pg. 5576-5590 (09 25 2018) ISSN: 1520-4995 [Electronic] United States
• PMID: 30148617 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Protein Kinase Inhibitors
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• Staurosporine
• midostaurin

Topics

• Animals
• BALB 3T3 Cells
• Cell Proliferation
• Cells, Cultured
• Fibroblasts (cytology, drug effects, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, enzymology, genetics, pathology)
• Mice
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Staurosporine (analogs & derivatives, pharmacology)
• fms-Like Tyrosine Kinase 3 (genetics)