Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

Leukemia
Barbara PeterP Valent

Abstract

Proteomic-based drug testing is an emerging approach to establish the clinical value and anti-neoplastic potential of multikinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC(50) values. Midostaurin and CGP62221 also produced growth inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, which accumulates in vivo, showed no substantial effects. Chemical proteomic profiling and drug competition experiments revealed that midostaurin interacts with KIT and several additional kinase targets. The key downstream regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgE receptor downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP5242...Continue Reading

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Citations

Nov 18, 2016·Expert Review of Hematology·Virginie De WildeOlivier Hermine
Jun 15, 2017·Future Oncology·Mrinal M Patnaik
Jun 21, 2019·International Journal of Molecular Sciences·Peter ValentMassimo Triggiani
Jun 15, 2017·Drugs·Esther S Kim
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Jul 15, 2018·Wiener klinische Wochenschrift·Peter ValentChristoph Zielinski
Apr 20, 2018·Case Reports in Hematology·Marta LopesMargarida Lima
Jan 8, 2017·Molecular Cancer Therapeutics·Branka Radic-SarikasGiulio Superti-Furga
Sep 3, 2019·The Journal of Allergy and Clinical Immunology·Catherine R WeilerLawrence B Schwartz
Oct 17, 2020·Expert Opinion on Biological Therapy·Jason GotlibAndreas Reiter
Feb 5, 2021·International Journal of Molecular Sciences·Jan RomantowskiPeter Valent
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Jun 25, 2021·The Journal of Allergy and Clinical Immunology. in Practice·Theo GülenPeter Valent
Nov 21, 2020·ACS Medicinal Chemistry Letters·Julia Shanu-WilsonJason Boer

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