Overview
MDM2 is a protein that helps control the levels of p53, a major tumor suppressor often called the cell’s “guardian of the genome.” In many cancers, including acute myeloid leukemia (AML), p53 itself is not mutated. Instead, its activity is switched off by excess MDM2, which leads to reduced tumor-suppressing function. This has made MDM2 an attractive treatment target in leukemias with wild-type TP53.
A major challenge with direct MDM2 inhibitors is that when they stabilize p53, they can also trigger a compensatory rise in MDM2. That feedback loop can weaken the drug’s effect and limit long-term benefit. This study examined whether a PROTAC-based MDM2 degrader could overcome that problem by removing the MDM2 protein rather than simply blocking it.
What PROTAC MDM2 degradation means
PROTAC stands for proteolysis-targeting chimera. These are engineered molecules designed to bring a disease-causing protein into contact with the cell’s own protein-disposal machinery. In this study, the compound MD-265 recruits CRBN, a component of an E3 ubiquitin ligase complex, to promote degradation of MDM2. By lowering MDM2 levels, the drug can restore p53 function and push leukemia cells toward apoptosis, or programmed cell death.
This approach is different from classic MDM2 inhibitors such as MI-1061, which mainly block the interaction between MDM2 and p53 without directly removing MDM2 from the cell.
Study design
The investigators tested MD-265 in ex vivo cultures of 105 primary leukemic stem cell samples. Leukemic stem cells are a clinically important population because they can sustain the disease, drive relapse, and contribute to resistance to therapy.
They also compared the effects of MD-265 with the MDM2 inhibitor MI-1061 and evaluated activity in normal hematopoietic stem cells to assess selectivity and potential toxicity. In addition, the team tested the compound in acute myeloid leukemia patient-derived xenograft (PDX) models implanted into NSG-SGM3 mice. PDX models are valuable because they preserve many of the biological features of the patient’s original leukemia.
Main findings in primary leukemia cells
MD-265 showed strong activity across the primary leukemia samples. The median cytotoxic IC50 was 16 nM, indicating that relatively low concentrations were enough to kill half of the leukemic cells in the tested samples.
By comparison, MI-1061 was much less potent, with a median IC50 about 150 times higher. This suggests that degrading MDM2 may be more effective than merely inhibiting it in this context.
A subset of leukemic stem cell samples had IC50 values above 1 µM and were classified as resistant to MD-265. These resistant samples were found to carry TP53 mutations. This is biologically consistent, because if p53 itself is mutated, removing MDM2 will not fully restore normal p53 tumor-suppressor activity.
Selectivity for leukemia cells over normal stem cells
An important question for any anti-leukemia therapy is whether it harms normal blood-forming stem cells. In this study, normal hematopoietic stem cells were much less sensitive to MD-265, with a median IC50 of 818 nM, about 100-fold higher than that seen in leukemic stem cells.
This difference suggests a therapeutic window in which the drug may preferentially target malignant cells while sparing normal hematopoiesis to a greater extent. That selectivity is especially important in AML, where treatment-related bone marrow suppression is a major concern.
Findings in PDX mouse models
The researchers next moved to in vivo testing using AML PDX models in NSG-SGM3 mice. MD-265 was not toxic in these animals and prolonged survival. This is a meaningful result because it indicates the compound has not only laboratory potency but also activity in a more realistic disease setting.
The study also compared MD-265 with an oral MDM2 inhibitor. While the detailed head-to-head clinical implications will require further investigation, the overall findings support the idea that a degrader strategy may offer advantages over inhibition alone, particularly by avoiding or reducing the feedback upregulation of MDM2.
Why this matters for AML treatment
AML remains a difficult disease to treat, especially in patients whose leukemia depends on intact p53 signaling being suppressed by MDM2. Although TP53 mutations occur in only a minority of AML cases, MDM2 overexpression can functionally silence wild-type p53 in many others.
Current treatment strategies that target the MDM2-p53 axis have shown promise, but resistance and limited durability remain major hurdles. By degrading MDM2 directly, MD-265 may provide a more complete restoration of p53 activity. That could translate into stronger anti-leukemia effects and potentially better durability than traditional inhibitors.
The finding that TP53-mutant cells were resistant also reinforces an important precision-medicine principle: patients most likely to benefit from MDM2-targeted treatment are those with wild-type TP53. In practice, TP53 mutation testing would likely be essential before considering such therapy.
Clinical and research implications
This study is preclinical, so it does not prove that MD-265 will work in patients. However, it provides several reasons for optimism:
The compound was highly potent in primary leukemia cells.
It was more active than a comparator MDM2 inhibitor.
It showed relative sparing of normal hematopoietic stem cells.
It prolonged survival in AML xenograft models.
Its activity aligned with the expected biology of p53 dependency.
At the same time, several questions still need to be answered before clinical use. These include pharmacokinetics, optimal dosing, long-term safety, effects on different AML subtypes, and whether the drug can be combined successfully with existing therapies such as venetoclax, hypomethylating agents, or standard chemotherapy.
It will also be important to understand whether resistance can emerge through additional mechanisms, such as alterations in the CRBN pathway, changes in drug transport, or broader p53 pathway rewiring.
Conclusion
MD-265 is a PROTAC-based MDM2 degrader that restored p53 function, induced leukemia cell death, and showed strong preclinical activity in primary AML samples and PDX models. Its potency, selectivity, and ability to bypass the feedback limitations of conventional MDM2 inhibitors make it a promising drug candidate for wild-type TP53 leukemias.
While further development is needed, this work supports a new strategy for targeting the MDM2-p53 axis in AML and potentially other cancers with intact p53 signaling.