MMRi62

MMRi62 is a degrader of murine double minute 2 (MDM2) and MDM4.¹ It induces ubiquitination of MDM2 and MDM4 in NALM6 leukemia cells when used at a concentration of 5 µM and selectively decreases the proliferation of MV4-11 leukemia cells (IC₅₀ = ~0.12 µM) over primary human peripheral blood mononuclear cells (PBMCs; IC₅₀ = ~15 µM). MMRi62 decreases the growth of HL-60 promyeoloblast leukemia cells and multidrug-resistant HL-60/DOX cells (IC₅₀s = 0.34 and 0.22 µM, respectively). It induces apoptosis in MV4-11 cancer cells when used at a concentration of 2 µM. MMRi62 decreases the number of colony-forming units (CFUs) in a panel of ten primary patient-derived leukemia cells expressing either wild-type or mutant p53 with mean IC₅₀ values of 11.7 and 12.8 µM, respectively. In vivo, MMRi62 (100 mg/kg per day) decreases tumor size in a HL-60/DOX mouse model of drug-resistant leukemia.

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1. Lama, R., Xu, C., Galster, S.L., et al. Small molecule MMRi62 targets MDM4 for degradation and induces leukemic cell apoptosis regardless of p53 status. Front. Oncol. 12, 933446 (2022).