MMRi62

MMRi62, a ferroptosis inducer targeting MDM2-MDM4 (negative regulators of tumor suppressor p53). MMRi62 shows a P53-independent pro-apoptotic activity against pancreatic ductal adenocarcinoma (PDAC) cells and induce autophagy. MMRi62 induces ferroptosis , resulting in a increase of reactive oxygen and lysosomal degradation of ferritin heavy chain (FTH1). 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. In Vitro MMRi62 inhibits proliferation, clonogenic, and spheroid growth of pancreatic ductal adenocarcinoma cell (PDAC) by induction of cell death. 1 MMRi62 (3 nM-100 μM;4 h) binds to RING–RINGheterodimers of MDM2 and MDM4 withthe K d value of 1.39 μM. MMRi62 (10 nM-1 μM;72 h) induces apoptosis and inhibits leukemic cells with IC 50 sof 0.34 µM (HL60) and 0.22 µM (HL60VR). MMRi62 (5 μM and 10μM; 24 h) decreases MDM2B autoubiquitination, increasesMDM4 ubiquitination in a dose-dependent manner. MMRi62 is an E3 ligase modifier capable ofswitching substrate preference from MDM2 to MDM4. MMRi62 (5 μM; 24and 72 h) induces apoptosis in a p53-independent manner. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: WT-p53 bearing MV4-11 cells; 293cells transfected with MDM2B and MDM4 Concentration: 2, 2.5, 5, 10, 40, 80, 160 μM Incubation Time: 24 hours Result: Increased cleaved PARP protein and activatedcaspase 3 level in wt-p53 bearing MV4-11 cells at 2 μM for 24 h. Decreased MDM2B autoubiquitination, increasedMDM4 ubiquitination at 5 μM and 10 μM for 24 h. Induced MDM2-dependent degradation of MDM4protein at 5 μM in NALM6 cells. Cell Proliferation AssayCell Line: Primary AML patient cells, NALM6cells and NALM6shp53 cells Concentration: 1, 10, 25, and 50 µM Incubation Time: 24 hours and 72 hours Result: Induced NALM6 cells apoptosis at 24 hand induced Primary AML patient cells at 72 h. In Vivo MMRi62 shows anti-tumor activity in orthotopic xenograft PDAC mouse models, by inhibiting tumor growth in mice associated with downregulation of NCOA4 and mutant p53 . MMRi62 also completely abrogates metastasis of orthotopic tumors . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Form:Solid

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