Download MendeleySAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors.
Karra, S., Xiao, Y., Chen, X., Liu-Bujalski, L., Huck, B., Sutton, A., Goutopoulos, A., Askew, B., Josephson, K., Jiang, X., Shutes, A., Shankar, V., Noonan, T., Garcia-Berrios, G., Dong, R., Dhanabal, M., Tian, H., Wang, Z., Clark, A., Goodstal, S.(2013) Bioorg Med Chem Lett 23: 3081-3087
- PubMed: 23570792
- DOI: https://doi.org/10.1016/j.bmcl.2013.03.008
- Primary Citation of Related Structures:
4JAI, 4JAJ - PubMed 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.
Organizational Affiliation:
EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, United States. Srinivasa.karra@emdserono.com
