PubMed Journals Articles About "Phase First Human Study Orally Administered Aurora Kinase" RSS

20:29 EST 20th January 2019 | BioPortfolio

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Showing "phase first human study orally administered Aurora kinase" PubMed Articles 1–25 of 78,000+

A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors.

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD)...

Structure-based drug design: Synthesis and biological evaluation of quinazolin-4-amine derivatives as selective Aurora A kinase inhibitors.

Aurora kinases play critical roles in the regulation of the cell cycle and mitotic spindle assembly. Aurora A kinase, a member of the Aurora protein family, is frequently highly expressed in tumors, and selective Aurora A inhibition serves as a significant component of anticancer therapy. However, designing highly selective Aurora A inhibitors is difficult because Aurora A and B share high homology and differ only by three residues in their ATP-binding pockets. Through structure-based drug design, we design...

Chromosome instability in tumor cells due to defects in Aurora B mediated error correction at kinetochores.

We characterized a panel of cancer cells and found that they exhibited chromosome instability (CIN) that was associated with high frequencies of aberrant kinetochore:microtubule attachments. Failure to resolve these defective attachments before anaphase onset can lead to missegregation of chromosomes. Aurora B kinase is concentrated at the inner centromere where it contributes to multiple kinetochore functions, one of which is in error-correction. Analysis of several CIN cell lines showed that many aspects ...

Effect of a non-systemic, orally-administered hydrogel, GS100, on metformin pharmacokinetics.

Overweight and obesity are major health concerns worldwide, and are major predisposing factors for type 2 diabetes. This single centre, Phase I, randomised, open-label, single-dose, four-arm crossover, device-drug interaction study on 24 healthy volunteers with a body mass index of 25-40 kg/m2 tested the effect of a novel, non-systemic, orally administered hydrogel (GS100) on the pharmacokinetics of the oral antidiabetic drug, metformin. When administered in both the fed and fasted states, the effect of GS1...

Pyrazolo4,3-bpyrimido4,5-e1,4diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR.

Aurora A, Aurora B and Kinase Insert Domain-containing Receptor (KDR) play essential roles in sustained cancer growth. In the present study, eighteen pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives were designed and synthesized. Most of the prepared compounds exhibited obviously enzymatic (Aurora A/B and KDR) activities. Among these analogs, compound 17g displayed significant Aurora A/B and KDR potencies with IC values of 46.2 nM, 37.6 nM and 21.6 nM, respectively. The results of further biol...

Correction: Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

[This corrects the article DOI: 10.1371/journal.pone.0164646.].

PK-PD based optimal dose and time for orally administered supra-pharmacological dose of melatonin to prevent radiation induced mortality in mice.

The study reports preclinical pharmacokinetics (PK) and correlation with pharmacological effect at suprapharmacological dose of orally administered melatonin along with time and dose optimization, which have been lacking in earlier reports of radioprotection using melatonin.

Phosphomimetic Mutation Destabilizes the Central Core Domain of Human p53.

Transcriptional activity of p53 is modulated by various posttranslational modifications. Earlier studies have reported that Aurora B phosphorylation of p53 leads to loss of its transcriptional activity, subsequently leading to its ubiquitin-mediated proteasomal degradation. To decipher the fate of structural and functional stature of p53 upon phosphorylation by Aurora B, we have generated five phosphomimetic mutants of p53 core domain and characterized their biophysicochemical properties. Our biophysical st...

The pharmacokinetics of orally administered butylscopolamine in greyhound dogs.

The oral tablet formulation of butylscopolamine, which is available without prescription, is commonly used by trainers of racing greyhounds to treat functional urethral obstruction. As medication control of butylscopolamine is therefore required for such use to ensure the integrity of greyhound racing, an administration study was performed in six greyhounds to determine the pharmacokinetics of orally administered butylscopolamine. A single dose of one 10 mg butylscopolamine tablet was administered orally t...

Validation of an LC-MS/MS method for simultaneous determination of icotinib and its four major circulating metabolites in human plasma and its application in a pharmacokinetic study.

In this study, a simple and sensitive LC-MS/MS method was developed and validated for simultaneous determination of icotinib and its four circulating metabolites in human plasma. The analytes were extracted with acetonitrile and separated on a C column using 2 mM ammonium acetate containing 0.2% formic acid and acetonitrile as mobile phase. The analytes were introduced into mass spectrometer via electrospray ionization source operated in positive ion mode. Precursor-to-product transitions were optimized to ...

A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.

Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galuniser...

Alterations in Pharmacokinetics of Orally Administered Carbamazepine in Rats Treated with Sodium alginate: Possible Interaction between Therapeutic Drugs and Semi-solid Enteral Nutrients.

The use of enteral nutrients plays an extremely important role in accurate nutrition management. Sodium alginate (SA) is frequently used for the semi-solidification of enteral nutrients. In the present study, we investigated whether the pharmacokinetic profile of orally administered carbamazepine (CBZ) is altered by a treatment with SA immediately before and after dosing of the drug. Furthermore, the adsorption effects of SA on CBZ were examined using an in vitro analysis.

Aurora kinase A localises to mitochondria to control organelle dynamics and energy production.

Many epithelial cancers show cell cycle dysfunction tightly correlated with the overexpression of the serine/threonine kinase Aurora A (AURKA). Its role in mitotic progression has been extensively characterised, and evidence for new AURKA functions emerges. Here, we reveal that AURKA is located and imported in mitochondria in several human cancer cell lines. Mitochondrial AURKA impacts on two organelle functions: mitochondrial dynamics and energy production. When AURKA is expressed at endogenous levels duri...

c-Myc is a major determinant for antitumor activity of Aurora A kinase inhibitor MLN8237 in thyroid cancer.

c-Myc is overexpressed in different types of cancer including thyroid cancer, and is considered undruggable over the decades. There is evidence showing that MLN8237, a kind of Aurora A kinase (AURKA) inhibitor, destabilizes c-Myc proteins in liver cancer cells through disrupting c-Myc/AURKA complex. However, the role of MLN8237 in thyroid cancer remains largely unclear. Our aims were to test therapeutic potential of MLN8237 in thyroid cancer, and to analyze determinant factors affecting the response of thyr...

Phase 1 Study of Edasalonexent (CAT-1004), an Oral NF-κB Inhibitor, in Pediatric Patients with Duchenne Muscular Dystrophy.

Edasalonexent is an orally administered small molecule designed to inhibit NF-κB, which is activated from infancy in Duchenne muscular dystrophy and is central to causing muscle damage and preventing muscle regeneration.

Orally administered heat-killed Lactobacillus paracasei MCC1849 enhances antigen-specific IgA secretion and induces follicular helper T cells in mice.

Antigen-specific immunoglobulin (Ig) A plays a major role in host defense against infections in gut mucosal tissue. Follicular helper T (Tfh) cells are located in germinal centers and promote IgA production via interactions with germinal center B cells. Several studies have demonstrated that some lactic acid bacteria (LAB) strains activate the host's acquired immune system, inducing IgA secretion in the intestine. However, the precise molecular mechanisms underlying the effects of LAB on IgA production and ...

Modulation of epigenetic factors during the early stages of HIV-1 infection in CD4 T cells in vitro.

Several studies have related epigenetic mechanisms to HIV-1 latency. However, the epigenetic modifications of the host cell genome involved in the early stages of HIV-1 infection remain unclear. This study aimed to investigate epigenetic factors that are regulated at the beginning of HIV-1 infection in activated and resting CD4 T cells. We analyzed the gene expression of 84 epigenetic targets, global DNA methylation, and HIV-1 replication kinetics for 36 h after infecting CD4 T cells obtained from the blo...

Tc-MDP as an imaging tool to evaluate the in vivo biodistribution of solid lipid nanoparticles.

The aim of this study was to establish the in vivo uptake and tissue distribution of Tc-MDP-encapsulated Solid Lipid Nanoparticles (SLNs) post administration. Radioactive Tc-MDP encapsulated into SLNs was administered to rats to trace their biodistribution through imaging and ex vivo studies. As expected IV injected Tc-MDP exhibited predominant visual bone uptake and a high localisation of particles in the kidneys (3.87%ID/g) followed by bone (2.66%ID/g). IV administered Tc-MDP encapsulated by SLN showed si...

The aurora named STEVE is not an aurora.

Inhibition of AURKA Reduces Proliferation and Survival of Gastrointestinal Cancer Cells With Activated KRAS by Preventing Activation of RPS6KB1.

Activation of KRAS signaling and overexpression of the aurora kinase A (AURKA) are often detected in luminal gastrointestinal cancers. We investigated regulation of ribosomal protein S6 kinase B1 (RPS6KB1) by AURKA and the effects of alisertib, an AURKA inhibitor, in mice xenograft tumors grown from human gastrointestinal cancer cells with mutant, activated forms of KRAS.

WAC Promotes Polo-like Kinase 1 Activation for Timely Mitotic Entry.

The key mitotic regulator Polo-like kinase 1 (Plk1) is activated during G2 phase by Aurora A kinase (AurkA)-mediated phosphorylation of its activation loop, which is important for timely mitotic entry. The mechanism for Plk1 activation remains incompletely understood. Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming...

The phytochemical and anti-inflammatory studies of Dillenia suffruticosa leaves.

The Dillenia suffruticosa leaves (Dilleniaceae), a folk medicine recommended in Southeast Asia for treating inflammation, were phytochemically studied for the first time and assessed for suppression of λ-carrageenan-induced paw oedema in rats. The crude methanolic extract orally administered at 5,000 mg/kg, displayed no toxicity and at 250 to 1,000 mg/kg significantly suppressed the paw oedema. Two-isolated triterpenoids, betulinic acid (1) and koetjapic acid (2) orally administered at 50 mg/kg, signifi...

Effect of carvacrol essential oils on immune response and inflammation-related genes expression in broilers challenged by lipopolysaccharide.

This experiment was conducted to study the effects of orally administered carvacrol essential oils on immune response and inflammation-related genes expression in broilers challenged by lipopolysaccharide (LPS). Eighty 28-day-old (1.28 ± 0.15 kg) ROSS 308 broilers were assigned to a 2 × 2 factorial arrangement of treatments (20 pens of 1 chick/trt). Factors were carvacrol essential oil (orally administered or non-orally administered) and LPS (challenged or non-challenged). Individually housed broilers we...

The EGF/hnRNP Q1 axis is involved in tumorigenesis via the regulation of cell cycle-related genes.

Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA-binding protein, has been implicated in many post-transcriptional processes, including RNA metabolism and mRNA splicing and translation. However, the role of hnRNP Q1 in tumorigenesis remains unclear. We previously performed RNA immunoprecipitation (RIP)-seq analysis to identify hnRNP Q1-interacting mRNAs and found that hnRNP Q1 targets a group of genes that are involved in mitotic regulation, including Aurora-A. Here, we demonstrate that altering t...

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity.

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