Design and Synthesis of Novel N‑(1H‑pyrazol-3-yl)pyrimidin-4-amine Aurora/HDAC Dual Inhibitors for Colorectal Cancer Treatment

Aurora kinase inhibitors show promise in treating solid tumors but face clinical limitations due to toxicity. To overcome these challenges, we designed and synthesized a series of dual Aurora/HDAC inhibitors to enhance antitumor efficacy through synergistic effects while reducing toxicity. Among them, compound 6 exhibited moderate inhibitory activity against HDAC1 (IC50 = 164 nM) and Aurora A (IC50 = 116 nM), however, it demonstrated potent antiproliferative effects across a variety of solid tumor and hematologic malignancy cell lines. Mechanistic studies confirmed it inhibited p-Aurora A, promoted Ac–H3, and induced apoptosis by arresting the cell cycle at the G2/M phase. In vivo, compound 6 displayed satisfactory bioavailability (F = 23.2%) and significantly suppressed tumor growth in the HCT-116 xenograft model (150 mg/kg/d, TGI = 71.8%) without apparent toxicity. These findings suggest that compound 6 is potential for further development in colorectal cancer therapy.