T is known that most of the newly developed anti-cancer compounds which are not good in vitro clinical stage due to various unfavorable factors such as pharmacokinetics and reduced power to progress in vivo. In this study we have shown that BPR1K653 exhibits favorable pharmacokinetic properties in vivo. The maximum plasma concentration achievable BPR1K653 after a single administration Givinostat ITF2357 at a dose of 5 mg / kg G body weight He than 80 times and 200 times the in vitro kinase inhibition IC 50 of Aurora kinase A and B respectively. Although at 24 hours after administration, plasma concentrations of BPR1K653 was still high enough for the activity T both Aurora A and Aurora B kinase inhibit. It also shows the high volume of distribution at station Their value, that the distribution of BPR1K653 in deep chambers of confinement Lich tumor tissue and expected.
Taken together, these favorable pharmacokinetic properties that BPR1K653 dosage t again Resembled sufficient for continuous inhibition of the activity t of both Aurora A and Aurora B kinase. Lockable End is a potent inhibitor AMPA inhibition of Aurora kinase BPR1K653 pan, in a position to cancer cells independently Ngig is their background tissue, MDR1, or p53 status target. These key features distinguish this compound from other already developed Aurora inhibitors and anti-cancer compounds. At the molecular level, the results of this study is that BPR1K653 as a tool for studying the molecular functions of Aurora kinases in cancer cells induces MDR1 resistant for use in the future.
How BPR1K653 has favorable pharmacokinetic properties in animal models, ben further evaluation To do prior to determining whether BPR1K653 is also effective in clinical situations. Materials and methods ethical statements animals were used in this study housed and experiments were performed at an International Association for Assessment KW 2449 and Accreditation of Laboratory Animal Care Facility Animal accredited National Institute conducted health research, Tainan, Taiwan, ROC Animal Protection and institutional bodies, the use of biotechnology and the National Health Research Institute approved uses of animals in these studies. The Aurora kinase inhibitor BPR1K653 Our studies of structure-activity Ts relationships and r Ntgenographische analysis were indentifed furanopyrimidine as a novel Aurora kinase inhibitor together.
The F Hre Aurora kinase inhibitor BPR1K653 was prepared from 4-chloro-6 phenylfuropyrimidine, which was originally obtained by a well-established three-step process synthesized. Cell culture of human cervical carcinoma KB cells, nasopharyngeal carcinoma 1 cells, colorectal carcinoma HT29 cells, oral squamous cell MECO 1, MV4 11 Leuk Been preconcentrated, purified HONE held IM9 myeloma cells in RPMI fed 1640 with 5% f Fetal K calf serum. The human lung adenocarcinoma A549 and NTUB1 the bladder cancer cells were fed in RPMI with 10% f Fetal calf serum K. KB-derived cell lines express MDR1 and NTUB1 dervided MDR1 cell line erg in a growth medium containing 10 nM vincristine, 15 nM and 17 nM paclitaxel Complements were maintained. KB cells were VIN10 in the study by the selection durchl, precious metals, vincristine and Amount of generated on the expression of Pgp170 / MDR1. KB and S15 NTU0