MMRi62 is a small molecule ferroptosis inducer and MDM2-MDM4-targeting chemical with p53-independent pro-apoptotic activity.
MMRi62 inhibits proliferation, clonogenic and spheroid growth of PDAC cells by induction of cell death (IC50=0.59-1.69 uM).
MMRi62-induced cell death in PDAC is characteristic of ferroptosis which is associated with increased autophagy, increased reactive oxygen species and lysosomal degradation of NCOA4 and Ferritin Heavy Chain (FTH1).
MMRi62 also induces proteasomal degradation of mutant p53.
MMRi62-induced ferroptosis occurs in PDAC cell lines harboring either KRAS and TP53 double mutations or single TP53 mutation.
MMRi62 inhibited tumor growth in mice associated with downregulation of NCOA4 and mutant p53 in orthotopic xenograft PDAC mouse models.
