SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors

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• 作者：Srinivasa Karra ; ^{Srinivasa.karra@emdserono.com} ; Yufang Xiao ; Xiaoling Chen ; Lesley Liu-Bujalski ; Bayard Huck ; Amanda Sutton ; Andreas Goutopoulos ; Ben Askew^§ ; ; Kristopher Josephson^&dagger ; ; Xuliang Jiang ; Adam Shutes^&Dagger ; ; Vikram Shankar ; Tom Noonan ; Gaianne Garcia-Berrios ; Rong Dong ; Mohanraj Dhanabal ; Hui Tian ; Zhenxiong Wang^¶ ; ; A. Clark ; Samantha Goodstal
• 关键词：Aurora kinase inhibitors ; Cancer ; Aurora kinase A ; Aurora kinase B ; Benzonapthyridinones ; DFG-out confirmation ; Endoreduplication ; phosphorylation of histone H3
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 May, 2013
• 年：2013
• 卷：23
• 期：10
• 页码：3081-3087
• 全文大小：2041 K

文摘

Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8]naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.