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Ref Type Journal Article
PMID (12124173)
Authors Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T, Gilliland DG, Griffin JD
Title Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412.
Journal Cancer cell
Vol 1
Issue 5
Date 2002 Jun
URL
Abstract Text Constitutively activating FLT3 receptor mutations have been found in 35% of patients with acute myeloblastic leukemia (AML). Here we report the identification of a small molecule FLT3 tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of Ba/F3 cell lines expressing mutant FLT3 (IC(50) < 10 nM) by directly inhibiting the tyrosine kinase. Ba/F3-FLT3 cell lines made resistant to PKC412 demonstrated overexpression of mutant FLT3, confirming that FLT3 is the target of this drug. Finally, progressive leukemia was prevented in PKC412-treated Balb/c mice transplanted with marrow transduced with a FLT3-ITD-expressing retrovirus. PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Midostaurin Midostaurin 51 11
Drug Name Trade Name Synonyms Drug Classes Drug Description
Midostaurin Rydapt PKC412|CGP 41251 CSF1R Inhibitor 24 FLT3 Inhibitor 55 KIT Inhibitor 51 PKC alpha Inhibitor 6 PKC beta Inhibitor 6 PKC Inhibitor (Pan) 10 VEGFR2 Inhibitor 35 Rydapt (midostaurin) is a multi-kinase inhibitor with activity against FLT3, KIT, PDGFRB, KDR (VEGFR2) and PKC, with higher selectivity for conventional PKC isoforms, which induces cell cycle arrest and apoptosis (PMID: 12124173, PMID: 23127174, PMID: 15914319). Rydapt (midostaurin) is FDA approved for FLT3-mutant AML in combination with chemotherapy, and is approved for use in aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia as a single therapy (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 D835Y Advanced Solid Tumor sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, treatment with Rydapt (midostaurin) inhibited FLT3 phosphorylation and resulted in decreased proliferation and viability of transformed cells expressing FLT3 D835Y in culture (PMID: 12124173). 12124173
FLT3 exon 14 ins Advanced Solid Tumor sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) demonstrated efficacy in inhibiting proliferation and viability of transformed cells expressing a FLT3-ITD mutation in culture (PMID: 12124173). 12124173
FLT3 wild-type Advanced Solid Tumor sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited FLT3 phosphorylation in transformed cells expressing wild-type FLT3 in culture (PMID: 12124173). 12124173