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.

本研究报道了一系列基于源自ENMD-2076的喹唑啉骨架的新型极光激酶（Aurora kinase）抑制剂的发现过程，以及乙烯基喹唑啉9h与极光A激酶（Aurora A）的首个X射线共晶复合物结构。将嘧啶环替换为喹唑啉环，不仅提升了化合物的抗癌活性，还促进了共晶的形成。化合物9a与9h均展现出优异的极光A激酶抑制活性，其半数抑制浓度（IC50）分别为6.0 nM与2.8 nM。9h对三阴性乳腺癌（TNBC）MDA-MB-231细胞展现出更优活性，其IC50值为48 nM；在异种移植模型中，9h可实现59%的肿瘤生长抑制率，而ENMD-2076的肿瘤生长抑制率仅为33%，且未表现出可观测的毒性。通过免疫印迹法、免疫荧光染色与流式细胞术开展的机制研究证实，9h在抑制极光A激酶激活、阻断纺锤体形成、阻滞细胞周期以及诱导细胞凋亡等方面均优于ENMD-2076。综上，9h具备进一步优化的潜力，是一款极具前景的抗癌候选药物。