ML162 is a covalent glutathione peroxidase 4 (GPX4) inhibitor that induces ferroptosis. ML162 has antitumor activity and selectively inhibits cell lines expressing mutant RAS oncogenes.

METHODS: Human lung cancer cells A549 were pretreated with ML162 (0.1-15 µM) for 4-24 h, and TXNRD1 activity was measured with the RX1 activity probe.
RESULTS: RX1 signaling was significantly inhibited dose-dependently at ML162 concentrations of 0.5 µM or higher. there was also a fairly rapid onset of concentration-dependent inhibition of cellular TXNRD1 activity, and incubation with 1 µM or higher ML162 treatment for 4 h was sufficient to inhibit RX1 signaling. mL162 effectively inhibited cellular TXNRD1 activity. ML162 effectively inhibits cellular TXNRD1 activity. ML162 effectively inhibited cellular TXNRD1 activity.[1]
METHODS: Melanoma cells A2058 and A375 were pretreated with ferrostatin (10 µM), Z-VAD-FMK (10 µM), or necrosulfonamide (0.5 µM) for 24 h. Cell viability was assayed after ML162 (1-16 µM) treatment.
RESULTS: ML162 caused cell death in a dose-dependent manner in the A2058 and A375 melanoma cell lines, which could be reversed by ferrostatin-1, a ferritin-specific inhibitor, but not by Z-VAD-FMK, an inhibitor of apoptosis, or necrosulfonamide, an inhibitor of necrotic apoptosis. [2]

METHODS: To detect anti-tumor activity in vivo, ML162 (40 mg/kg once daily) and anti-PD-1 antibody (200 µg every three days) were intraperitoneally injected into BALB/c mice bearing TS/A tumors once daily for two weeks.
RESULTS: The combination of GPX4 inhibitor and anti-PD-1 antibody significantly inhibited tumor growth compared with monotherapy. The combination therapy did not result in additional immune cell infiltration compared to monotherapy, but the combination therapy induced a significant immune response with an increased proportion of PRF1+CD8+ T cells and GZMB+CD8+ T cells. [3]