SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors |
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| Authors: | Srinivasa Karra Yufang Xiao Xiaoling Chen Lesley Liu-Bujalski Bayard Huck Amanda Sutton Andreas Goutopoulos Ben Askew Kristopher Josephson Xuliang Jiang Adam Shutes Vikram Shankar Tom Noonan Gaianne Garcia-Berrios Rong Dong Mohanraj Dhanabal Hui Tian Zhenxiong Wang Samantha Goodstal |
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| Affiliation: | EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, United States |
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| Abstract: | 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. |
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| Keywords: | Aurora kinase inhibitors Cancer Aurora kinase A Aurora kinase B Benzonapthyridinones DFG-out confirmation Endoreduplication phosphorylation of histone H3 |
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