EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, United States.
Bioorg Med Chem Lett. 2013 May 15;23(10):3081-7. doi: 10.1016/j.bmcl.2013.03.008. Epub 2013 Mar 13.
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.
几种来源于 5H-苯并[c][1,8]萘啶-6-酮骨架的强效 Aurora 激酶抑制剂被鉴定出来。 Aurora 激酶 A 与初始命中物复合物的晶体结构揭示了抑制剂在 ATP 结合位点内的结合模式，并为基于结构的化合物优化提供了深入了解。随后的 SAR 研究提供了一种强效且选择性的 pan Aurora 抑制剂，该抑制剂在胰腺细胞系 MIAPaCa-2 中表现出有效的靶标调节和抗增殖作用。此外，该化合物在口服给药后可抑制小鼠骨髓中组蛋白 H3 的磷酸化（pHH3），这与 Aurora 激酶 B 活性的抑制一致。
