An MDM2 degrader for treatment of acute leukemias
Bridget K Marcellino1, Xiaobao Yang2, H Ümit Kaniskan2
1Department of Medicine, Division of Hematology Oncology and Tisch Cancer Institute (TCI), Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY, USA.
Abstract:
In acute myeloid leukemia (AML), p53 tumor suppressor activity can be reduced due to enhanced expression of MDM2 which promotes the degradation of p53. In TP53 wild-type malignancies, therapy with small molecule antagonists of MDM2 results in antileukemic activity. Current treatment strategies, however, have been limited by poor tolerability and incomplete clinical activity. We have developed a proteolysis-targeting chimera (PROTAC) MS3227 that targets MDM2 by recruiting the E3 ligase Von Hippel-Lindau, resulting in proteasome-dependent degradation of MDM2. In WT TP53 leukemia cell lines, MS3227 led to activation of p53 targets p21, PUMA, and MDM2 and resulted in cell-cycle arrest, apoptosis, and decreased viability. The catalytic PROTAC MS3227 led to more potent activation when compared to a stoichiometric inhibitor, in part by dampening the negative feedback mechanism in the p53 - MDM2 circuit. The effectiveness of MS3227 was also observed in primary patient specimens with selectivity towards leukemic blasts. The addition of MS3227 enhanced the activity of other anti-leukemic agents including azacytidine, cytarabine, and venetoclax. In particular, MS3227 treatment was shown to downregulate MCL-1, a known mediator of resistance to venetoclax. A PROTAC-based approach may provide a means of improving MDM2 inhibition to gain greater therapeutic potential in AML.
Insights
A novel PROTAC therapy, MS3227, effectively degrades MDM2 in acute myeloid leukemia (AML) cells, activating p53 and enhancing anti-leukemic activity. This approach shows promise for improving AML treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- MDM2 overexpression in acute myeloid leukemia (AML) inhibits the p53 tumor suppressor, promoting leukemic cell survival.
- Targeting MDM2 with small molecule inhibitors has shown antileukemic activity in TP53 wild-type AML, but clinical efficacy is limited by tolerability and incomplete responses.
Purpose of the Study:
- To develop and evaluate a novel proteolysis-targeting chimera (PROTAC), MS3227, for targeted degradation of MDM2 in AML.
- To assess the efficacy of MS3227 in vitro and in primary patient samples, and to investigate its potential to overcome resistance to existing therapies.
Main Methods:
- Development of MS3227, a PROTAC designed to recruit the Von Hippel-Lindau E3 ligase for proteasomal degradation of MDM2.
- In vitro studies using WT TP53 leukemia cell lines to assess p53 target activation, cell-cycle arrest, apoptosis, and viability.
- Evaluation of MS3227 in primary AML patient specimens and in combination with standard AML agents (azacytidine, cytarabine, venetoclax).
Main Results:
- MS3227 induced potent degradation of MDM2, leading to activation of p53 targets (p21, PUMA, MDM2), cell-cycle arrest, apoptosis, and decreased viability in AML cell lines.
- MS3227 demonstrated superior efficacy compared to stoichiometric inhibitors by overcoming negative feedback in the p53-MDM2 pathway.
- The PROTAC showed selectivity for leukemic blasts in primary patient samples and enhanced the activity of azacytidine, cytarabine, and venetoclax, notably downregulating MCL-1, a venetoclax resistance mediator.
Conclusions:
- MS3227 represents a promising therapeutic strategy for AML by catalytically degrading MDM2 and reactivating p53.
- The PROTAC approach offers potential for improved tolerability and efficacy over conventional MDM2 inhibitors.
- MS3227 may overcome resistance mechanisms, particularly to venetoclax, by downregulating MCL-1, suggesting a significant therapeutic potential in AML treatment.
Related Concept Videos
02:23Abnormal Proliferation
01:15Differentiation of Common Myeloid Progenitor Cells