Fast-forwarding hit to lead: Aurora and epidermal growth factor receptor kinase inhibitor lead identification

Mohane Selvaraj Coumar, Chang Ying Chu, Cheng Wei Lin, Hui Yi Shiao, Yun Lung Ho, Randheer Reddy, Wen Hsing Lin, Chun Hwa Chen, Yi Hui Peng, Jiun Shyang Leou, Tzu Wen Lien, Chin Ting Huang, Ming Yu Fang, Szu Huei Wu, Jian Sung Wu, Santhosh Kumar Chittimalla, Jen Shin Song, John T.A. Hsu, Su Ying Wu, Chun Chen LiaoYu Sheng Chao, Hsing Pang Hsieh

研究成果: Article同行評審

57 引文 斯高帕斯(Scopus)


A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

頁(從 - 到)4980-4988
期刊Journal of Medicinal Chemistry
出版狀態Published - 2010 七月 8

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 藥物發現


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