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1.
Diabetes Obes Metab ; 20(9): 2113-2120, 2018 09.
Article in English | MEDLINE | ID: mdl-29707866

ABSTRACT

AIMS: To investigate the pharmacokinetics and pharmacodynamics of a dual-acting glucokinase activator, dorzagliatin, and its safety, tolerability and effect on pancreatic ß-cell function in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 24 T2D patients were selected, utilizing a set of predefined clinical biomarkers, and were randomized to receive dorzagliatin 75 mg twice or once daily (BID, QD respectively) for 28 days. Changes in HbA1c and glycaemic parameters from baseline to Day 28 were assessed. In addition, changes in ß-cell function from baseline to Day 32 were evaluated. RESULTS: Significant reductions in HbA1c were observed in both regimens on Day 28 (-0.79%, 75 mg BID; -1.22%, 75 mg QD). Similar trends were found in the following parameters, including reductions from baseline in fasting plasma glucose by 1.20 mmol/L and 1.51 mmol/L, in 2-hour postprandial glucose by 2.48 mmol/L and 5.03 mmol/L, and in glucose AUC0-24 by 18.59% and 20.98%, for the BID and QD groups, respectively. Both regimens resulted in improvement in ß-cell function as measured by steady state HOMA 2 parameter, %B, which increased by 36.31% and 40.59%, and by dynamic state parameter, ΔC30 /ΔG30 , which increased by 24.66% and 167.67%, for the BID and QD groups, respectively. Dorzagliatin was well tolerated in both regimens, with good pharmacokinetic profiles. CONCLUSIONS: Dorzagliatin treatment for 28 days in Chinese T2D patients, selected according to predefined biomarkers, resulted in significant improvement in ß-cell function and glycaemic control. The safety and pharmacokinetic profile of dorzagliatin supports a subsequent Phase II trial design and continued clinical development.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Enzyme Activators/therapeutic use , Glucokinase/metabolism , Hypoglycemic Agents/therapeutic use , Patient Selection , Pyrazoles/pharmacology , Biomarkers/blood , Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Female , Glycated Hemoglobin/analysis , Humans , Insulin-Secreting Cells/drug effects , Male , Middle Aged , Pyrazoles/therapeutic use , Treatment Outcome
2.
Mol Cancer Ther ; 7(8): 2386-93, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18723485

ABSTRACT

Aurora kinases have emerged as promising targets for cancer therapy because of their critical role in mitosis. These kinases are well-conserved in all eukaryotes, and IPL1 gene encodes the single Aurora kinase in budding yeast. In a virtual screening attempt, 22 compounds were identified from nearly 15,000 microbial natural products as potential small-molecular inhibitors of human Aurora-B kinase. One compound, Jadomycin B, inhibits the growth of ipl1-321 temperature-sensitive mutant more dramatically than wild-type yeast cells, raising the possibility that this compound is an Aurora kinase inhibitor. Further in vitro biochemical assay using purified recombinant human Aurora-B kinase shows that Jadomycin B inhibits Aurora-B activity in a dose-dependent manner. Our results also indicate that Jadomycin B competes with ATP for the kinase domain, which is consistent with our docking prediction. Like other Aurora kinase inhibitors, Jadomycin B blocks the phosphorylation of histone H3 on Ser10 in vivo. We also present evidence suggesting that Jadomycin B induces apoptosis in tumor cells without obvious effects on cell cycle. All the results indicate that Jadomycin B is a new Aurora-B kinase inhibitor worthy of further investigation.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Aurora Kinase B , Aurora Kinases , Blotting, Western , Cell Line , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Flow Cytometry , Histones/antagonists & inhibitors , Histones/metabolism , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Molecular Structure , Phosphorylation , Protein Kinase Inhibitors/chemistry , Recombinant Proteins/antagonists & inhibitors
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