Identification,SAR Studies,and X‐ray Co‐crystallographic Analysis of a Novel Furanopyrimidine Aurora Kinase A Inhibitor |
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Authors: | Mohane Selvaraj Coumar Dr Ming‐Tsung Tsai Chang‐Ying Chu Dr Biing‐Jiun Uang Dr Wen‐Hsing Lin Dr Chun‐Yu Chang Teng‐Yuan Chang Jiun‐Shyang Leou Chi‐Huang Teng Dr Jian‐Sung Wu Ming‐Yu Fang Chun‐Hwa Chen John T‐A Hsu Dr Su‐Ying Wu Dr Yu‐Sheng Chao Dr Hsing‐Pang Hsieh Dr |
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Affiliation: | 1. Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan (Republic of China), Fax: (+886)?37‐586‐456;2. Department of Chemistry, National Tsing Hua University, 101, Sect. 2, Guangfu Road, Hsinchu 300, Taiwan (Republic of China);3. Department of Biological Science and Technology, National Chiao Tung University, 1001 University Road, Hsinchu 300, Taiwan (Republic of China) |
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Abstract: | Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in‐house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in‐house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC50 values ranging from ~300 nM to ~15 μM , by testing only 133 compounds from a database of ~125 000 compounds. Structure–activity relationship studies and X‐ray co‐crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC50 value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors. |
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Keywords: | aurora kinase inhibitors hit identification structural biology structure– activity relationships substructure searches |
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