An MDM2 degrader shows potent cytotoxicity to MDM2-overexpressing acute lymphoblastic leukemia cells with minimal
Tao Liu1, Lubing Gu1, Anna Mui1
1Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Abstract:
The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression through both p53-dependent and -independent pathways. Here, we report a novel small-molecule chemical compound (MX69-102) that we identified to induce MDM2 protein degradation, resulting in reactivation of p53, inhibition of XIAP, and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL) in vitro and in vivo. We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modifications of MX69 and selected analog MX69-102, showing increased MDM2-targeting activity. MX69-102 exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC50 values of about 0.2 μM, representing an approximately 38-fold increase in activity compared to MX69. MX69-102 also showed effective inhibition on xenografted human MDM2-overexpressing ALL in SCID mice. Importantly, MX69-102 had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-102 is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory/MDM2-overexpressing ALL.
Insights
A new drug, MX69-102, effectively targets and degrades MDM2 protein, a key factor in cancer progression. This leads to cancer cell death and shows promise as a targeted therapy for acute lymphoblastic leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- MDM2 oncogene amplification/overexpression drives cancer progression via p53-dependent and -independent pathways.
- Elevated MDM2 protein functions as a survival factor in various human cancers.
Purpose of the Study:
- To report a novel small-molecule compound, MX69-102, designed to induce MDM2 protein degradation.
- To evaluate the therapeutic potential of MX69-102 in MDM2-overexpressing acute lymphoblastic leukemia (ALL).
Main Methods:
- Structural modification of a previously identified MDM2-targeting compound (MX69) to develop MX69-102.
- In vitro assessment of MX69-102's effects on ALL cell lines, including IC50 determination.
- In vivo evaluation of MX69-102 efficacy in xenografted human ALL models in SCID mice.
- Assessment of MX69-102's impact on normal human hematopoiesis and in vivo tolerability.
Main Results:
- MX69-102 demonstrated significantly enhanced MDM2-targeting activity compared to MX69, with IC50 values around 0.2 μM against ALL cell lines.
- The compound induced potent cell growth inhibition and apoptosis in MDM2-overexpressing ALL cells.
- MX69-102 showed effective inhibition of xenografted human ALL in vivo.
- Minimal toxicity to normal hematopoiesis in vitro and good tolerability in vivo were observed.
Conclusions:
- MX69-102 effectively induces MDM2 protein degradation, reactivates p53, and inhibits XIAP.
- The compound exhibits potent anti-leukemic activity against MDM2-overexpressing ALL with a favorable safety profile.
- MX69-102 represents a promising candidate for developing novel MDM2-targeted therapeutics for refractory/MDM2-overexpressing ALL.
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