Coumar, Mohane Selvaraj Chu, Chang-Ying Lin, Cheng-Wei Shiao, Hui-Yi Ho, Yun-Lung Reddy, Randheer Lin, Wen-Hsing Chen, Chun-Hwa Peng, Yi-Hui Leou, Jiun-Shyang Lien, Tzu-Wen Huang, Chin-Ting Fang, Ming-Yu Wu, Szu-Huei Wu, Jian-Sung Chittimalla, Santhosh Kumar Song, Jen-Shin Hsu, John T.-A. Wu, Su-Ying Liao, Chun-Chen Chao, Yu-Sheng Hsieh, Hsing-Pang Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification 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 <b>1a</b> was modified to better fit the back pocket, producing the potent Aurora inhibitor <b>3</b> with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit <b>1s</b>, introduction of acrylamide Michael acceptor group led to <b>8</b>, 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 <b>3</b> and <b>8</b> 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. docking studies;basis;binding modes;kinase activity;identification;epidermal growth factor receptor;HCT;Aurora inhibitor 3;EGFR kinase;library construction;submicromolar antiproliferative activity;antiproliferative activity;HCC 827 lung cancer cell line;biology observations;Epidermal Growth Factor Receptor Kinase Inhibitor;acrylamide Michael acceptor group;SBDD 2010-07-08
    https://acs.figshare.com/articles/journal_contribution/Fast_Forwarding_Hit_to_Lead_Aurora_and_Epidermal_Growth_Factor_Receptor_Kinase_Inhibitor_Lead_Identification/2754058
10.1021/jm1000198.s001