Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A.

[Display omitted] • Novel AurkA allosteric inhibitors of N -benzylbenzamide backbone were designed and synthesized. • The most potent analogue 6 h (AurkA IC 50 = 6.50 μM) was comparable to the activity of AurkinA, the most potent AurkA allosteric inhibitor. • 6 h dissipated the interaction between AurkA and its activator TPX2 by binding to the Y-pocket of AurkA. • 6 h suppressed the DNA replication during G/S transition, which is a non-catalytic function of AurkA. • Docking analysis of 6 h showed several crucial interactions with the residues in Y-pocket and was well-coherent with the structure–activity relationship. Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6 h) of N -benzylbenzamide backbone. Compound 6 h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6 h against AurkA (IC 50 = 6.50 μM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure–activity relationship. In addition, 6 h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors. [ABSTRACT FROM AUTHOR]