MD-224 is a first-in-class and highly potent small-molecule human murine double minute 2 (MDM2) degrader based on the proteolysistargeting chimera (PROTAC) concept. MD-224 has the potential to be a new class of anticancer agent.
MD-224 is a first-in-class and highly potent small-molecule human murine double minute 2 (MDM2) degrader based on the proteolysistargeting chimera (PROTAC) concept. MD-224 has the potential to be a new class of anticancer agent.
Targets
Target
Value
Cell Research
Cell Line
Type
Value
Description
References
In Vitro
MDM2 Degradation & p53 Induction: MD-224 (1-30 nM; 2 hours) effectively induces depletion of MDM2 protein and concurrent accumulation of p53 protein in a dose-dependent manner in RS4;11 cells [1].
Transcriptional Upregulation: MD-224 (30 nM; 6 hours) is significantly more potent than MI-1061 in the induction of transcriptional upregulation of p53 target genes (e.g., CDKN1A, PUMA, and BAX) but has no effect on TP53 mRNA levels in RS4;11 cells [1].
Apoptosis Induction: MD-224 (0.001-1 uM; 24 hours) induces robust apoptosis at concentrations <= 10 nM in a dose-dependent manner upon a 24-hour treatment in RS4;11 cells [1].
Cell Growth Inhibition: MD-224 (1 nM - 10 uM; 4 days) inhibits cell proliferation with an IC50 of 1.5 nM in RS4;11 cells and 15 nM in SJSA-1 cells, while showing no activity (IC50 > 10 uM) in p53-mutated or p53-deleted cell lines [1].
Mechanism Confirmation: MD-224 (10-100 nM; 1 hour) mediated MDM2 degradation is completely blocked by pre-treatment with MG132 (20 uM) or MLN4924 (1 uM), confirming the degradation is proteasome-dependent [1].
In Vivo
Tumor Regression (RS4;11 Model): MD-224 (25, 50, or 100 mg/kg; IV; every other day for 2 weeks) achieves complete and durable tumor regression in the RS4;11 subcutaneous xenograft model in mice [1].
Sustained Response: In the RS4;11 model, tumors treated with MD-224 (50 mg/kg) do not regrow for over 60 days after the treatment is stopped, demonstrating superior efficacy compared to small-molecule inhibitors [1].
Tumor Regression (SJSA-1 Model): MD-224 (25, 50, or 100 mg/kg; IV; every other day for 3 weeks) induces complete tumor regression in the SJSA-1 osteosarcoma xenograft model, which is a p53-WT model with MDM2 amplification [1].
Pharmacodynamics (PD): A single dose of MD-224 (25-100 mg/kg; IV) effectively induces rapid and prolonged depletion of MDM2 protein and significant accumulation of p53 and p21 proteins in tumor tissues [1].
Toxicity and Body Weight: MD-224 is well-tolerated at efficacious doses (25-100 mg/kg), with no significant body weight loss or obvious toxicity observed in the treated mice during the study period [1].
Pharmacokinetics (PK): Following a single IV dose of 5 mg/kg in mice, MD-224 shows a moderate half-life (t1/2 = 4.0 hours) and a high volume of distribution, indicating good tissue distribution [1].
References
[1] Li Y, et al. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression. J Med Chem. 2019 Jan 24;62(2):448-466. PMID: 30521364.
Store lyophilized at -20ºC, keep desiccated. In lyophilized form, the chemical is stable for 36 months. In solution, store at -20ºC and use within 1 months to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.
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