Compounds 9h(Sun Yat-sen University/Guangzhou University of Chinese Medicine)

This work describes the discovery of a new series of Aurora kinase inhibitors based on quinazoline skeleton derived from ENMD-2076, as well as the first X-ray cocrystal structure complexes of vinyl-quinazoline 9h with Aurora A. Replacing pyrimidine with quinazoline improved anticancer activity and facilitated cocrystal formation. Compounds 9a and 9h showed excellent Aurora A kinase inhibition, with IC₅₀ values of 6.0 and 2.8 nM, respectively. 9h demonstrated superior activity against TNBC MDA-MB-231 cells with an IC₅₀ value of 48 nM and achieved 59% tumor growth inhibition in xenograft models, vs ENMD-2076's 33% with no observable toxicity. Mechanistic studies using immunoblotting, immunofluorescence staining, and flow cytometry showed that 9h outperforms ENMD-2076 in inhibiting Aurora A kinase activation, preventing spindle formation, arresting the cell cycle, and inducing cell apoptosis. Thus, 9h has the potential for further optimization and is a promising anticancer drug candidate.