Design, Synthesis and Evaluation of 4-Methoxy-1H-[1,2,3]triazolo[4,5-c]quinolines as Highly Potent and Oral Available RIOK2 Inhibitors.

RIOK2 is a promising therapeutic target in cancer due to its pivotal role in tumor progression. Based on our previously identified RIOK2 inhibitor CQ211, we conducted a comprehensive pharmacokinetic optimization campaign, leading to the discovery of CQ3196 as a potent and orally bioavailable RIOK2 inhibitor. CQ3196 demonstrates remarkable RIOK2 binding affinity, with a Kd value of 14 nM, and exhibits potent proliferative inhibitory activities in gastric cancer cell lines. Furthermore, CQ3196 displays favorable PK properties, it achieves an AUC(0-t) value of 3.5 × 103 μg/L·h following oral administration, ensuring sufficient drug exposure for therapeutic efficacy. Additionally, it achieves robust in vivo antitumor efficacy in an HGC-27 gastric cancer xenograft model. Oral administration of CQ3196 at 50 mg/kg resulted in a TGI value of 62.3%, highlighting its strong therapeutic potential. These compelling results underscore CQ3196 as a highly promising candidate for further development in RIOK2-targeted cancer therapy.