Identification, SAR studies, and X-ray Co-crystallographic analysis of a novel furanopyrimidine aurora kinase a inhibitor

Mohane Selvaraj Coumar, Ming Tsung Tsai, Chang Ying Chu, Biing Jiun Uang, Wen Hsing Lin, Chun Yu Chang, Teng Yuan Chang, Jiun Shyang Leou, Chi Huang Teng, Jian Sung Wu, Ming Yu Fang, Chun Hwa Chen, John T.A. Hsu, Su Ying Wu, Yu Sheng Chao, Hsing Pang Hsieh

研究成果: Article同行評審

23 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)255-267
頁數13
期刊ChemMedChem
5
發行號2
DOIs
出版狀態Published - 2010 二月 1

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子醫學
  • 藥理
  • 藥物發現
  • 藥理學、毒理學和藥劑學 (全部)
  • 有機化學

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