GPX4 (R)-9i

GPX4 (R)-9i is a ferroptosis inducer. It binds to GPX4 in a cellular thermal shift assay (CETSA) using HT-1080 fibrosarcoma cells (Kd = 20. nM) and inhibits GPX4 activity in a cell-free assay. It is cytotoxic to HT-1080 cells, an effect that can be reversed by the ferroptosis inhibitor ferrostatin-1 (IC50s = 0. and 7,482 nM, respectively). The cytotoxicity of GPX4 (R)-9i to HT-1080 cells is not reversed by the addition of Z-VAD-FMK, indicating selectivity for ferroptosis over apoptosis. It is also cytotoxic to HepG2 hepatocellular carcinoma, MCF-7 breast cancer, CAL 27 oral cancer, and 4T1 murine mammary cancer cells (IC50s = 56, 452, 2,682, and 89 nM, respectively). GPX4 (R)-9i (15 and 30 mg/kg) reduces tumor growth in an HT-1080 mouse xenograft model. InChI: InChI=1S/C29H24N4O3S2/c1-5-25-31-22(16-38-25)28(35)33(19-12-10-18(11-13-19)23-14-30-17-36-23)26(27(34)32-29(2,3)4)21-15-37-24-9-7-6-8-20(21)24/h1,6-17,26H,2-4H3,(H,32,34)/t26-/m1/s1, InChIKey: NBLAYHIFDLIFHK-AREMUKBSSA-N, SMILES: CC(C)(C)NC([C@@H](C1=CSC2=CC=CC=C21)N(C3=CC=C(C=C3)C4=CN=CO4)C(C5=CSC(C#C)=N5)=O)=O