【摘 要】
：
We have recently reported furano-pyrimidine Aurora kinase A inhibitor 3(ligand efficiency,LE=0.25;liphophilic efficiency,LipE=1.75),with potent activity in vitro;however,3 was inactive in vivo.Based o
【机 构】
：
Institute of Biotechnology and Pharmaceutical Research,National Health Research Institutes
【出 处】
：
第九届IUPAC化学生物学国际研讨会暨第八届世界华人药物化学研讨会
论文部分内容阅读
We have recently reported furano-pyrimidine Aurora kinase A inhibitor 3(ligand efficiency,LE=0.25;liphophilic efficiency,LipE=1.75),with potent activity in vitro;however,3 was inactive in vivo.Based on the insight from the X-ray cocrystal structure of the lead 3,various solubilizing functional groups were introduced to optimize both the activity and drug-like property.Emphasis was placed on identifying compounds with optimal LE and LipE,two important criteria for further development as drug candidates,by leveraging both the molecular weight and liphophilicity of the molecules.Intensive lead optimization has resulted in the identification of Aurora kinase inhibitor 18 with improved potency and physicochemical property(LE=0.27;LipE=4.98),along with significant in vivo antiproliferative activity in HCT-116(colon cancer) tumor xenografl mouse model.
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