MDM2 and MDM4 have established cancer drug targets. Additionally, they are also inhibitors of p53 activity and are amplified in many cancer types. In particular, the targeting of MDM2–p53 interactions is a novel strategy that is pursued to unleash the antitumor activity of p53. Furthermore,  there needs to cover more potent, small-molecule inhibitors of MDM2–p53 interactions.

In this article, we will introduce a potent ferroptosis inducer targeting MDM2-MDM4.

MMRi62, a ferroptosis inducer targeting MDM2-MDM4 (negative regulators of tumor suppressor p53). Additionally, it binds to RING–RINGheterodimers of MDM2 and MDM4 with a K_d value of 1.39 μM. MMRi62 shows a P53-independent pro-apoptotic activity against pancreatic ductal adenocarcinoma (PDAC) cells and induces Autophagy. MMRi62 induces Ferroptosis, resulting in an increase of reactive oxygen and lysosomal degradation of ferritin heavy chain (FTH1). Additionally, MMRi62 also leads to proteasomal degradation of mutant p53, also inhibits orthotopic xenograft PDAC mouse model in vivo with high-frequency mutation characteristics of KRAS and TP53.12. MMRi62 inhibits proliferation, clonogenic, and spheroid growth of pancreatic ductal adenocarcinoma cells (PDAC) by induction of cell death. MMRi62  induces apoptosis and inhibits leukemic cells with IC₅₀sof 0.34 µM (HL60) and 0.22 µM (HL60VR), respectively. Additionally, MMRi62 is an E3 ligase modifier capable of switching substrate preference from MDM2 to MDM4. In WT-p53 bearing MV4-11 cells; 293 cells transfected with MDM2B and MDM4, as a result, MMRi62 decreases MDM2B autoubiquitination, and increases MDM4 ubiquitination in a dose-dependent manner. MMRi62 (5 μM; 24 and 72 h) induces apoptosis in a p53-independent manner. Additionally,  it increases cleaved PARP protein and activated caspase 3 level in wt-p53 bearing MV4-11 cells at 2 μM for 24 h. MMRi62 shows anti-tumor activity in orthotopic xenograft PDAC mouse models. As a result, it inhibits tumor growth in mice associated with the downregulation of NCOA4 and mutant p53. MMRi62 also completely abrogates metastasis of orthotopic tumors. All in all, MMRi62 shows potent apoptotic and anti-tumor activity and can be used for cancer research.