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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. | ||||||||||||
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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 |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Midostaurin | Midostaurin | 110 | 13 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Midostaurin | Rydapt | PKC412|CGP 41251 | CSF1R Inhibitor 28 FLT3 Inhibitor 69 KIT Inhibitor 57 PKC alpha Inhibitor 6 PKC beta Inhibitor 6 PKC Inhibitor (Pan) 11 VEGFR2 Inhibitor 37 | 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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 |
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 |