DEL-I25 is a selective, small molecule activator of GPX4 R152H variant, selectively binds to GPX4 R152H (MST binding KD, 2 uM), restores GPX4R152H enzyme activity, and specifically rescues patient-derived lymphoblast cells.
DEL-I25 shows little to no actiivty against GPX4 WT (MST KD, >100 uM)
DEL-I25 can boost the viability of patient lymphoblast RAG03 to 520%, with EC50 of 2 uM.
DEL-I25 (100 uM) fully restores the enzymatic activity of GPX4R152H to 96% of GPX4WT.
At the concentration of EC100 (10 μM), DEL-I25 is more therapeutically effective than general antioxidants α-tocopherol and CoQ10.
DEL-I25 can stabilize the G-loop in GPX4R152H, which contains residue W136 essential for GPX4 enzymatic activity and is disordered by the R152H mutation.
