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

  • Bioorg Med Chem Lett. 2013 May 15;23(10):3081-7. doi: 10.1016/j.bmcl.2013.03.008.
Srinivasa Karra  1 ,  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 ,  A Clark ,  Samantha Goodstal
Affiliations
  • 1. EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, United States. [email protected]
PMID: 23570792 DOI: 10.1016/j.bmcl.2013.03.008
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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