MD-4251
MD-4251 is an orally active MDM2 PROTAC degrader with a DC50 of 0.2 nM in RS4;11 cells. MD-4251 induces cereblon-dependent depletion and degradation of MDM2 protein, elevates p53 protein levels and activates p53. MD-4251 inhibits the proliferation of wild-type p53 acute leukemia cells, induces complete and durable tumor regression in xenograft models, and upregulates the protein levels of DSC1, NBEA and CASP14. MD-4251 can be used in studies related to acute leukemia.
(Pink: MDM2 ligand (HY-130684); Blue: Cereblon ligand (HY-W883326); Black: linker).
Nur für Forschungszwecke. Wir verkaufen nicht an Patienten.
- Formel: C47H53Cl2FN8O4
- Molecular Weight:883.88
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
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Biologische Aktivität
Beschreibung
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MDM2 0.2 nM (DC50) |
p53 |
DSC1 |
NBEA |
CASP14 |
In Vitro
MD-4251 potently inhibits the growth of wild-type p53 acute leukemia cell lines RS4;11 (IC50 = 1 nM), MV4;11 (IC50 = 2 nM), and MOLM-13 (IC50 = 2 nM), while showing minimal activity against the mutated p53 cell line RS4;11/IRMI2 (IC50 > 1000 nM)[1].
MD-4251 (≥3 nM; 2 h) degrades MDM2 in RS4;11 cells with a DC50 of 0.2 nM and 96% maximal degradation within 2 h, while increasing p53 protein levels by over 6-fold at concentrations of 3 nM or higher[1].
MD-4251 upregulates p53, DSC1, NBEA, and CASP14 protein levels in MV4;11 and MOLM-13 cells, with no detectable MDM2 depletion due to low baseline MDM2 expression[1].
MD-4251 (0.03-300 nM; 2 h) potently degrades MDM2 with a DC50 of 0.2 nM and Dmax of 96% in RS4;11 cells after 2 h, accompanied by robust p53 upregulation, while showing minimal effects on other cereblon neo-substrates[2].
MD-4251 (Serial dilutions; 4 days) inhibits RS4;11 cell growth with an IC50 of 1 nM, and this activity is dependent on cereblon binding[2].
MD-4251 (Serial dilutions; 4 days) inhibits MV4;11 cell growth with an IC50 of 2 nM[2].
MD-4251 (Serial dilutions; 4 days) inhibits MOLM-13 cell growth with an IC50 of 2 nM[2].
MD-4251 (3 nM; 2 h) upregulates p53 and three additional proteins (DSC1, NBEA, CASP14) in RS4;11 cells, with no protein depleted by more than 2-fold[2].
MD-4251 exhibits excellent metabolic stability in liver microsomes and plasma from multiple species, with a half-life exceeding 60 min across all tested samples[1].
MD-4251 (1 μM; Up to 60 min) demonstrates excellent microsomal and plasma stability (T1/2 >60 min) in human, mouse, rat, dog, and monkey samples[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:RS4;11 human acute leukemia cell line (wild-type p53)
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Concentration:0.03-300 nM
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Incubation Time:2 h
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Result:Induced potent MDM2 degradation with a DC50 of 0.2 nM and a maximum degradation (DMAX) of 96% at 2 h.
Depleted MDM2 protein by >70% at 0.3 nM.
Increased p53 protein levels by >6-fold at 3 nM or higher concentrations.
Reduced MDM2 degradation at concentrations ≥100 nM, while p53 upregulation remained robust.
Showed no effect on GSPT1 or IKZF3 levels.
Exerted only a modest effect on IKZF1 and CK1α levels.
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Cell Line:RS4;11 human acute leukemia cell line (wild-type p53)
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Concentration:Serial dilutions
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Incubation Time:4 days
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Result:Potently inhibited RS4;11 cell growth with an IC50 of 1 nM.
Lost cell growth inhibition activity (IC50 >100 nM) when co-treated with 10 μM of the cereblon ligand RKA-4237.
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Cell Line:MV4;11 human acute leukemia cell line (wild-type p53)
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Concentration:Serial dilutions
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Incubation Time:4 days
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Result:Potently inhibited MV4;11 cell growth with an IC50 of 2 nM.
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Cell Line:MOLM-13 human acute leukemia cell line (wild-type p53)
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Concentration:Serial dilutions
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Incubation Time:4 days
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Result:Potently inhibited MOLM-13 cell growth with an IC50 of 2 nM.
Parmacokinetics
In Vivo
MD-4251 (10-30 mg/kg; p.o.; single dose) induces sustained MDM2 depletion and p53 pathway activation in RS4;11 xenograft tumors in female SCID mice, with effects persisting for at least 72 hours at a 30 mg/kg dose[2].
MD-4251 (60 mg/kg; p.o.; single dose) does not induce thrombocytopenia in female BALB/c mice[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:SCID (female)[2]
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Dosage:3 mg/kg (3x/week); 3 mg/kg (1x/week); 10 mg/kg (1x/week); 50 mg/kg (single dose)
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Administration:p.o.; three times a week; 3 weeks; p.o.; once weekly; 3 weeks; p.o.; single dose
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Result:Inhibited tumor growth by 91% at 3 mg/kg three times weekly and 10 mg/kg once weekly at the end of the 3-week treatment period.
Inhibited tumor growth by 53% at 3 mg/kg once weekly at the end of the 3-week treatment period.
Induced rapid and complete tumor regression with a single oral dose of 50 mg/kg, with no detectable tumors remaining in all mice 24 days after regression was achieved.
Caused no significant weight loss or other signs of toxicity across all doses.
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Animal Model:SCID (female)[2]
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Dosage:10 mg/kg; 30 mg/kg
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Administration:p.o.; single dose
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Result:Depleted MDM2 protein to 35% and 29% of vehicle control levels in tumor tissue at 6 and 24 hours post 10 mg/kg single oral dose, respectively.
Increased p53 protein to 179% of control at 24 hours post 10 mg/kg single oral dose.
Increased cleaved PARP to 235% of control at 24 hours post 10 mg/kg single oral dose.
Induced sustained MDM2 depletion at 24, 48, and 72 hours post 30 mg/kg single oral dose, accompanied by robust increases in p53 and PUMA protein levels in tumor tissue.
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Animal Model:BALB/c (female)[2]
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Dosage:60 mg/kg
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Administration:p.o.; single dose
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Result:Did not significantly reduce platelet counts compared to control treatment.
Chemical Information
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Molecular Weight 883.88
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Formel C47H53Cl2FN8O4
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SMILES
O=C1NC2=CC(Cl)=CC=C2[C@]13C4(CCCCC4)N[C@H]([C@@H]3C5=CC=CC(Cl)=C5F)C(N[C@@H]6CC[C@H](CC6)CN7CCN(CC7)C8=CC=C9C(N(N=C9C%10C(NC(CC%10)=O)=O)C)=C8)=O
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
[1]. Wu S, et al. MDM2 Degrader as a Promising Therapeutic Strategy for Cancer Treatment. Journal of medicinal chemistry. 2025 Jul 10;68(13):13246-13248. [Content Brief]
[2]. Acharyya RK, et al. MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration. Journal of medicinal chemistry. 2025 Jul 10;68(13):13249-13267. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
MD-4251 Related Classifications
HY-174458 Related Classifications
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