Abstract
This dissertation is concerned with the development of indazole-based derivatives as Aurora kinases inhibitors. Based on the concept of ATP competitive inhibitors, indazole skeleton was selected as a starting point. Utilizing our in-house database by sub-structure screening, hit compound 47 was identified as the initial hit which showed weak inhibition against Aurora A. Compound 50a was further synthesized by using in silico FBDD techniques and resulting in 10-fold potency improvement. Following by rational drug design, the carboxylic acid group extended from aniline at the C-3 of indazole core and phenylsulfonamide group at the C-5 of indazole core are newly identified to improve the potency as lead compound 74. SAR of lead compound 74 was constructed as well as the drug-like property was modified to enhance activity against cancer cell proliferation. Finally, kinases profiling and isoform selectivity were assayed and discussed through computer assisted docking model.