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

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

Affiliation

  • 1 EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, United States. Srinivasa.karra@emdserono.com
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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