Design and synthesis of (E)-3-benzylideneindolin-2-one derivatives as potential allosteric inhibitors of Aurora A kinase.

Abstract

The mitotic kinase Aurora A, a pivotal regulator of the cell cycle, is overexpressed in various cancers and has emerged as one of the most promising targets for anticancer drug discovery. However, the lack of specificity and potential toxicity have impeded clinical trials involving orthosteric inhibitors. In this study, allosteric sites of Aurora A were predicted using the AlloReverse web server. Based on the non-ATP competitive inhibitor Tripolin A and molecular docking information targeting the desired allosteric site 3 of Aurora A, a series of (E)-3-benzylideneindolin-2-one derivatives were designed and synthesized. Compared to Tripolin A, our compounds AK09, AK34 and AK35 have stronger inhibitory effects and can be further investigated as potential allosteric inhibitors. Moreover, the compound AK34 with the strongest inhibitory activity (IC₅₀ = 1.68 μM) has a high affinity for Aurora A (K _D = 216 nM). According to the analysis of the structure-activity relationship of the compounds and the results of their molecular docking models, these compounds tend to act on the allosteric site 3 of Aurora A.