Abstract MDM2 is an E3 ubiquitin ligase that promotes p53 tumor suppressor degradation and has emerged as a therapeutic target in the treatment of wild-type (wt) TP53 tumors. In acute myeloid leukemia (AML), TP53 mutations are infrequent (15–20%), but wt-p53 is often inactivated through overexpression of MDM2. Thus, MDM2 inhibitors are currently in clinical trials for AML. However, p53 stabilization with inhibitors upregulates MDM2, which limits their clinical efficacy. Proteolysis-targeting chimeric (PROTAC) molecules that degrade MDM2 may overcome this feedback. MD-265 is a PROTAC that recruits CRBN, degrades MDM2, restores p53 and induces apoptosis. We tested MD-265 in ex vivo cultures of 105 primary leukemic stem cells (LSCs). The median cytotoxic IC 50 for MD-265 was 16 nM, median IC 50 for MI-1061 was 150-fold higher. LSCs with IC 50 > 1 µM were classified as MD-265 resistant and harbored mutations in TP53. Normal hematopoietic stem cells showed 100-fold higher IC 50 (818 nM) than LSCs. AML patient-derived xenograft (PDX) models in NSG-SGM3 mice were treated with MD-265 or an oral MDM2 inhibitor. In PDX models, MD-265 was not toxic and prolonged survival. MD-265 is a potent and specific MDM2 degrader with broad pre-clinical activity and a promising drug candidate for the treatment of leukemias.
Kandarpa et al. (Wed,) studied this question.