352693-80-2

MMRi62 is an MDM4-degrader and apoptosis inducer in leukemia cells. MMRi62 targets MDM4 for degradation and induces leukemic cell apoptosis regardless of p53 status. MMRi62 effectively induced apoptosis in p53 mutant, multidrug-resistant leukemia cells and patient samples in addition to p53 wild-type cells. In contrast, MMRi67 as a RING heterodimer disruptor and an enzymatic inhibitor of the MDM2-MDM4 E3 complex lacked MDM4-degrader activity and failed to induce apoptosis in these cells.

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 inducesferroptosis, 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[1][2].

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[1] Li J, et al. Small-Molecule MMRi62 Induces Ferroptosis and Inhibits Metastasis in Pancreatic Cancer via Degradation of Ferritin Heavy Chain and Mutant p53. Mol Cancer Ther. 2022 Apr 1;21(4):535-545. DOI:10.1158/1535-7163.MCT-21-0728
[2] Lama R, et al. Small molecule MMRi62 targets MDM4 for degradation and induces leukemic cell apoptosis regardless of p53 status. Front Oncol. 2022 Aug 5;12:933446. DOI:10.3389/fonc.2022.933446