u-0126 has been researched along with trametinib* in 5 studies
5 other study(ies) available for u-0126 and trametinib
Article | Year |
---|---|
The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice.
Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Butadienes; Cell Proliferation; Cisplatin; Kidney; Lipocalin-2; Lung Neoplasms; MAP Kinase Signaling System; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Neoplasm Proteins; Nitriles; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tumor Burden | 2020 |
Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis.
Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance. Topics: Adolescent; Adrenal Cortex Hormones; Butadienes; Combined Modality Therapy; Cytarabine; Disease Progression; Drug Resistance; Drug Therapy, Combination; Enzyme Activation; Exons; HEK293 Cells; Hematopoietic Stem Cell Transplantation; Histiocytosis, Langerhans-Cell; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Molecular Targeted Therapy; Mutation; Nitriles; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrazoles; Pyridones; Pyrimidinones; Recombinant Fusion Proteins; Sequence Deletion; Thiophenes; Vincristine | 2018 |
Genome-Wide CRISPR Screen Identifies Regulators of Mitogen-Activated Protein Kinase as Suppressors of Liver Tumors in Mice.
It has been a challenge to identify liver tumor suppressors or oncogenes due to the genetic heterogeneity of these tumors. We performed a genome-wide screen to identify suppressors of liver tumor formation in mice, using CRISPR-mediated genome editing.. We identified 4 candidate liver tumor suppressor genes not previously associated with liver cancer (Nf1, Plxnb1, Flrt2, and B9d1). CRISPR-mediated knockout of Nf1, a negative regulator of RAS, accelerated liver tumor formation in mice. Loss of Nf1 or activation of RAS up-regulated the liver progenitor cell markers HMGA2 and SOX9. RAS pathway inhibitors suppressed the activation of the Hmga2 and Sox9 genes that resulted from loss of Nf1 or oncogenic activation of RAS. Knockdown of HMGA2 delayed formation of xenograft tumors from cells that expressed oncogenic RAS. In human HCCs, low levels of NF1 messenger RNA or high levels of HMGA2 messenger RNA were associated with shorter patient survival time. Liver cancer cells with inactivation of Plxnb1, Flrt2, and B9d1 formed more tumors in mice and had increased levels of mitogen-activated protein kinase phosphorylation.. Using a CRISPR-based strategy, we identified Nf1, Plxnb1, Flrt2, and B9d1 as suppressors of liver tumor formation. We validated the observation that RAS signaling, via mitogen-activated protein kinase, contributes to formation of liver tumors in mice. We associated decreased levels of NF1 and increased levels of its downstream protein HMGA2 with survival times of patients with HCC. Strategies to inhibit or reduce HMGA2 might be developed to treat patients with liver cancer. Topics: Animals; Benzimidazoles; Blotting, Western; Butadienes; Carcinoma, Hepatocellular; Cell Line, Tumor; CRISPR-Cas Systems; Cytoskeletal Proteins; DNA, Neoplasm; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Genes, Neurofibromatosis 1; Genome-Wide Association Study; Hepatocytes; High-Throughput Nucleotide Sequencing; HMGA Proteins; HMGA2 Protein; Humans; Immunohistochemistry; Liver Neoplasms; Liver Neoplasms, Experimental; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Nude; Mitogen-Activated Protein Kinases; Nerve Tissue Proteins; Niacinamide; Nitriles; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Pyridones; Pyrimidinones; ras Proteins; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface; Sequence Analysis, DNA; Sorafenib; Survival Analysis; Tumor Suppressor Protein p53; Tumor Suppressor Proteins | 2017 |
ERK Plays a Role in Chromosome Alignment and Participates in M-Phase Progression.
Cell division, a prerequisite for cell proliferation, is a process in which each daughter cell inherits one complete set of chromosomes. The mitotic spindle is a dedicated apparatus for the alignment and segregation of chromosomes. Extracellular signal-regulated kinase (ERK) 1/2 plays crucial roles in cell cycle progression, particularly during M-phase. Although, association with the mitotic spindle has been reported, the precise roles played by ERK in the dynamics of the mitotic spindle and in M-phase progression remain to be elucidated. In this study, we used MEK inhibitors U0126 and GSK1120212 to dissect the roles of ERK in M-phase progression and chromosome alignment. Fluorescence microscopy revealed that ERK is localized to the spindle microtubules in a manner independent of Src kinase, which is one of the kinases upstream of ERK at mitotic entry. ERK inhibition induces an increase in the number of prophase cells and a decrease in the number of anaphase cells. Time-lapse imaging revealed that ERK inhibition perturbs chromosome alignment, thereby preventing cells from entering anaphase. These results suggest that ERK plays a role in M-phase progression by regulating chromosome alignment and demonstrate one of the mechanisms by which the aberration of ERK signaling may produce cancer cells. Topics: Anaphase; Animals; Butadienes; Cell Line; Chromosomes, Human; Extracellular Signal-Regulated MAP Kinases; Humans; Nitriles; Prophase; Pyridones; Pyrimidinones; Spindle Apparatus; Swine; Time-Lapse Imaging | 2016 |
Identification and characterization of a novel chemotype MEK inhibitor able to alter the phosphorylation state of MEK1/2.
A small molecule compound, JTP-74057/GSK1120212/trametinib, had been discovered as a very potent antiproliferative agent able to induce the accumulation of CDK inhibitor p15INK4b. To conduct its drug development rationally as an anticancer agent, molecular targets of this compound were identified as MEK1/2 using compound-affinity chromatography. It was shown that JTP-74057 directly bound to MEK1 and MEK2 and allosterically inhibited their kinase activities, and that its inhibitory characteristics were similar to those of the known and different chemotype of MEK inhibitors PD0325901 and U0126. It was further shown that JTP-74057 induced rapid and sustained dephosphorylation of phosphorylated MEK in HT-29 colon and other cancer cell lines, while this decrease in phosphorylated MEK was not observed in PD0325901-treated cancer cells. Physicochemical analyses revealed that JTP-74057 preferentially binds to unphosphorylated MEK (u-MEK) in unique characteristics of both high affinity based on extremely low dissociation rates and ability stabilizing u-MEK with high thermal shift, which were markedly different from PD0325901. These findings indicate that JTP-74057 is a novel MEK inhibitor able to sustain MEK to be an unphosphorylated form resulting in pronounced suppression of the downstream signaling pathways involved in cellular proliferation. Topics: Allosteric Regulation; Antineoplastic Agents; Benzamides; Butadienes; Chromatography, Affinity; Diphenylamine; Dose-Response Relationship, Drug; HEK293 Cells; HT29 Cells; Humans; Kinetics; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Nitriles; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction | 2012 |