Optimization of Novel Quinazolines as Potent Aurora Kinase Inhibitors for Triple-Negative Breast Cancer Treatment

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.