NCI677397 is a USP24 inhibitor. It enhances lipid ROS, activates cholesterol and fatty acid biosynthesis, and degrades ABC transporters, GPX4, and DHFR through the autophagy pathway. This process reduces p-gp levels, ultimately leading to ferroptosis in drug-resistant cancer cells. NCI677397 is relevant for research in lung and brain cancers.

NCI677397 demonstrates potent efficacy in reversing multidrug resistance in various cancer cell types, including paclitaxel-resistant T24 lung cancer, temozolomide (TMZ)-resistant Pt3-TMZR and U87-R brain cancer, camptothecin (CPT)-resistant Hone-1-CPTR nasopharyngeal carcinoma, and oxaliplatin-resistant HCT116-OXR colorectal carcinoma across a concentration range of 0-120 nM for 24 hours to 7 days. At concentrations of 10 and 20 μM over 4 days, NCI677397 significantly reduces the viability of both TMZ-sensitive and resistant glioblastoma cells and exhibits synergistic effects when combined with TMZ. The compound at 0-20 μM for 24 hours induces autophagy in both TMZ-sensitive and resistant glioblastoma, as well as in A549 cells and paclitaxel-resistant A549 (A549-T24) cells, without triggering apoptosis. Additionally, at concentrations of 0-15 μM over 24 hours, it induces biosynthesis of cholesterol and fatty acids in Pt’3, Pt’3R, U87, U87R, A549, and A549-T24 cells. NCI677397 (0-25 μM, 24 h) mediates ferroptosis in U87, U87R, Pt'3, Pt'3R, and A549-T24 cells through lipid reactive oxygen species. The compound also degrades ABCG1/5/8 via the autophagy pathway and reduces the stability of GPX4 and DHFR in Pt'3R and A549-T24 cells. At 20 μM over 0-24 hours, it induces lipid peroxidation within 2 hours, upregulates cholesterol synthase after 6 hours, and completes the ferroptosis process by 24 hours in Pt’3R cells.

In the U87R xenograft mouse model, NCI677397Z (20 mg/kg, i.p., administered twice a week for 7 weeks) significantly inhibited tumor growth.