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

Biochemistry
Paul W ManleyMarkus Wartmann

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, PD...Continue Reading

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Citations

Nov 23, 2017·Leukemia & Lymphoma·Mrinal M Patnaik
Jan 23, 2020·Journal of Cellular and Molecular Medicine·Ellen WeisbergJames D Griffin
Jan 27, 2019·Expert Review of Anticancer Therapy·Amro ElshouryEunice S Wang
Nov 30, 2019·Journal of Clinical Pharmacy and Therapeutics·Robert ManciniFinn Petersen
Sep 3, 2019·Cancer Cell·Miguel Reina-CamposJorge Moscat
Jul 8, 2021·Cancer Discovery·David J YoungDonald Small

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