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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|