pyrimidinones and midostaurin

pyrimidinones has been researched along with midostaurin* in 2 studies

Other Studies

2 other study(ies) available for pyrimidinones and midostaurin

Article	Year
MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia. Scientific reports, 2019, 12-09, Volume: 9, Issue:1 FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML. Topics: Adult; Aged; Animals; Antigens, CD34; Bone Marrow Cells; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Male; MAP Kinase Kinase Kinase 1; MAP Kinase Signaling System; Mice; Middle Aged; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Staurosporine	2019
In Vitro Screening of Six Protein Kinase Inhibitors for Time-Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug-Drug Interactions. Basic & clinical pharmacology & toxicology, 2018, Volume: 123, Issue:6 Topics: Benzamides; Benzimidazoles; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Indoles; Inhibitory Concentration 50; Microsomes, Liver; Phthalazines; Piperidines; Pyridines; Pyridones; Pyrimidinones; Quinolones; Staurosporine; Thiazoles	2018

Article

Year

MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia.

Scientific reports, 2019, 12-09, Volume: 9, Issue:1

FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.

Topics: Adult; Aged; Animals; Antigens, CD34; Bone Marrow Cells; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Male; MAP Kinase Kinase Kinase 1; MAP Kinase Signaling System; Mice; Middle Aged; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Staurosporine

2019

In Vitro Screening of Six Protein Kinase Inhibitors for Time-Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug-Drug Interactions.

Basic & clinical pharmacology & toxicology, 2018, Volume: 123, Issue:6

Topics: Benzamides; Benzimidazoles; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Indoles; Inhibitory Concentration 50; Microsomes, Liver; Phthalazines; Piperidines; Pyridines; Pyridones; Pyrimidinones; Quinolones; Staurosporine; Thiazoles

2018