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Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models
Malathi Kandarpa1,2, Luke F Peterson1, Harish Potu1
1Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
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 IC50 for MD-265 was 16 nM, median IC50 for MI-1061 was 150-fold higher. LSCs with IC50 > 1 µM were classified as MD-265 resistant and harbored mutations in TP53. Normal hematopoietic stem cells showed 100-fold higher IC50 (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.
Insights
MD-265, a novel PROTAC molecule, effectively degrades MDM2 and restores p53 function, showing potent anti-leukemic activity in preclinical models. This approach overcomes resistance seen with traditional MDM2 inhibitors in acute myeloid leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- MDM2 is an E3 ubiquitin ligase targeting p53 for degradation, crucial in wild-type TP53 cancers like acute myeloid leukemia (AML).
- MDM2 inhibitors are in clinical trials for AML but face efficacy limitations due to feedback-induced MDM2 upregulation.
- Proteolysis-targeting chimeras (PROTACs) offer a strategy to degrade MDM2, potentially overcoming this resistance mechanism.
Purpose of the Study:
- To evaluate the efficacy of MD-265, a novel MDM2-degrading PROTAC, in preclinical models of leukemia.
- To assess the selectivity and therapeutic potential of MD-265 compared to existing MDM2 inhibitors.
Main Methods:
- Ex vivo testing of MD-265 on 105 primary leukemic stem cells (LSCs) and normal hematopoietic stem cells.
- Assessment of MD-265 efficacy and toxicity in acute myeloid leukemia patient-derived xenograft (PDX) models in mice.
- Comparison of MD-265 with a standard oral MDM2 inhibitor in PDX models.
Main Results:
- MD-265 demonstrated potent cytotoxicity against LSCs with a median IC50 of 16 nM, significantly lower than the comparator MI-1061.
- MD-265 exhibited selectivity, with normal hematopoietic stem cells showing a 100-fold higher IC50.
- TP53-mutated LSCs were resistant to MD-265.
- In PDX models, MD-265 was well-tolerated and prolonged survival without toxicity.
Conclusions:
- MD-265 is a potent and specific MDM2 degrader with significant preclinical activity in leukemia models.
- MD-265 represents a promising therapeutic candidate for leukemia treatment, particularly by overcoming MDM2 inhibitor resistance.
- The selectivity of MD-265 for leukemic cells over normal stem cells suggests a favorable therapeutic window.
