國家衛生研究院 NHRI:Item 3990099045/7352

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Title:	Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine aurora kinase inhibitor
Authors:	Shiao, HY;Coumar, MS;Chang, CW;Ke, YY;Chi, YH;Chu, CY;Sun, HY;Chen, CH;Lin, WH;Fung, KS;Kuo, PC;Huang, CT;Chang, KY;Lu, CT;Hsu, JT;Chen, CT;Jiaang, WT;Chao, YS;Hsieh, HP
Contributors:	Institute of Biotechnology and Pharmaceutical Research;Institute of Cellular and Systems Medicine
Abstract:	Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.
Date:	2013-06-28
Relation:	Journal of Medicinal Chemistry. 2013 Jun 28;56(13):5247-5260.
Link to:	http://dx.doi.org/10.1021/jm4006059
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000321884200003
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84880175303
Appears in Collections:	[Hsing-Pang Hsieh] Periodical Articles [Yu-Sheng Chao(2002-2013)] Periodical Articles [Weir-Torn Jiaang] Periodical Articles [Chiung-Tong Chen] Periodical Articles [John Tsu-An Hsu] Periodical Articles [Ya-Hui Chi] Periodical Articles

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