Discovery of Potent and Selective Pyrrolo[2,3-d]Pyrimidine-Based Aurora A Inhibitors with Demonstrated Efficacy against Patient-Derived Gastric Cancer Organoids.

Aurora A kinase, a key regulator of mitosis, has emerged as a promising therapeutic target for gastric cancer. However, challenges related to selectivity and resistance highlight the urgent need for novel Aurora A inhibitors with improved profiles. In this study, we rationally designed and synthesized a series of pyrrolo[2,3-d]pyrimidine-based Aurora A inhibitors via scaffold hopping and structural optimization of Alisertib. Among them, compound 11 demonstrated potent Aurora A inhibitory activity (IC50 = 0.74 nM) and improved selectivity over Aurora B compared to Alisertib. It also exhibited strong antiproliferative effects in gastric cancer cell lines and superior efficacy in patient-derived gastric cancer organoids (IC50 = 3.5 μM), outperforming Alisertib. These findings suggest that compound 11 is a highly potent and selective Aurora A inhibitor with significant therapeutic potential for gastric cancer treatment.