Discovery of a Potent and Highly Selective Inhibitor of Aurora A Kinase.

Aurora kinase A, a serine-threonine kinase frequently overexpressed in cancers, remains unaddressed by clinically approved inhibitors. Our previously endeavors unveiled a unique class of quinazolin-4-amine derivatives as potent, selective Aurora A kinase inhibitors. To further enhance therapeutic potential and Aurora A selectivity, we conducted systematic structural optimization and developed compound 5h, which exhibits potent antiproliferative activity across human cancer cell linesparticularly in triple-negative breast cancer MDA-MB-231 cells. Crucially, 5h exhibits 362-fold selectivity for Aurora A over Aurora B, a critical feature for therapeutic efficacy and safety. Molecular dynamics simulations reveal its selectivity arises from unique C-H/π interactions, enhanced hydrophobic contacts, an open Aurora A binding pocket, and tighter protein packing. At submicromolar concentrations, 5h effectively suppresses Aurora A autophosphorylation. Furthermore, it significantly inhibits tumor growth in MDA-MB-231 xenograft models, supporting its development as a promising anticancer candidate.