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Spotlight on midostaurin in the treatment of FLT3-mutated acute myeloid leukemia and systemic mastocytosis: design, development, and potential place in therapy

Authors Weisberg E, Sattler M, Manley PW, Griffin JD

Received 28 September 2017

Accepted for publication 14 November 2017

Published 29 December 2017 Volume 2018:11 Pages 175—182

DOI https://doi.org/10.2147/OTT.S127679

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Carlos E Vigil


Ellen Weisberg,1,2 Martin Sattler,1,2 Paul W Manley,3 James D Griffin1,2

1Department of Medical Oncology, Dana-Farber Cancer Institute, 2Department of Medicine, Harvard Medical School, Boston, MA, USA; 3Department of Oncology, Novartis Institutes of Biomedical Research, Basel, Switzerland

Abstract: The Fms-like tyrosine kinase-3 (FLT3; fetal liver kinase-2; human stem cell tyrosine kinase-1; CD135) is a class III receptor tyrosine kinase that is normally involved in regulating the proliferation, differentiation, and survival of both hematopoietic cells and dendritic cells. Mutations leading it to be constitutively activated make it an oncogenic driver in ~30% of acute myeloid leukemia (AML) patients where it is associated with poor prognosis. The prevalence of oncogenic FLT3 and the dependency on its constitutively activated kinase activity for leukemia growth make this protein an attractive target for therapeutic intervention. Of the numerous small molecule inhibitors under clinical investigation for the treatment of oncogenic FLT3-positive AML, the N-benzoyl-staurosporine, midostaurin (CGP41251; PKC412; Rydapt®; Novartis Pharma AG, Basel, Switzerland), is the first to be approved by the US Food and Drug Administration for the treatment, in combination with standard chemotherapy, of newly diagnosed adult AML patients who harbor mutations in FLT3. Here, we describe the early design of midostaurin, the preclinical discovery of its activity against oncogenic FLT3, and its subsequent clinical development as a therapeutic agent for FLT3 mutant-positive AML.

Keywords: AML, acute myeloid leukemia, PKC412, midostaurin, FLT3-ITD, oncogenic FLT3, targeted therapy

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