TopoisomeraseI inhibitor 17 (Compound 7h) is an inhibitor of TopoisomeraseI (Top1). It reduces DDX5 and reverses the locking effect of DDX5 on Top1 activity. This compound induces Top1-mediated DNA damage and promotes reactive oxygen species (ROS) production. It triggers apoptosis by decreasing anti-apoptotic proteins XIAP, Bcl-2, and Survivin, while increasing pro-apoptotic proteins Bax and γH2AX. Moreover, TopoisomeraseI inhibitor 17 halts progression at the G2/M checkpoint, leading to cell cycle arrest. It significantly impairs colorectal cancer cell colony formation and migration, and effectively reduces tumor size in human PDX tumor mouse models.

Topoisomerase I inhibitor 17 exhibits antiproliferative effects on four cancer cell lines (HepG2, A549, HeLa, and HCT116) with IC50 values of 136.6, 33.7, 72.9, and 36.1 nM, respectively, when used at 5-500 nM for 72 hours. It can permeate Caco-2 cell monolayers with an apparent permeability coefficient of 2.24 μcm/s (0.5-1.0 μM, 4 h), maintaining over 90% cell viability (0.2-1.0 μM, 4 h). The inhibitor (5-100 nM, 12-72 h) significantly curtails proliferation-induced colony formation, inhibits HCT116 cell migration in a concentration-dependent manner, and increases ROS production. At concentrations of 0-50 μM over 48 hours, it induces apoptosis and cell cycle arrest in HCT116 cells, halting progression at the G2/M checkpoint. Additionally, it suppresses DDX5 expression in HCT116 cells (100 μM, 48-72 h) and alleviates DDX5-mediated Top1 activity inhibition at concentrations of 5 and 50 μM.

Topoisomerase I inhibitor 17, administered intraperitoneally at doses of 2-15 mg/kg once weekly for four weeks, effectively reduces tumor size in human colon cancer PDX mouse models. This effect is achieved through a concentration-dependent tumor inhibition with tolerable toxicity.