In vitro: HDM201 binds to the p53 binding-site of the Mdm2 protein, disrupting the interaction of the two proteins and leading to the activation of the p53 pathway. It induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. HDM201 exhibits highly selectivity across a panel of cancer cell lines.
In vivo: HDM201 displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability. Application of the compound using various dosing schedules triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancers.
| Cell Experiment | |
|---|---|
| Cell lines | Melanoma cells |
| Preparation method | Melanoma cells were seeded in 96-well plates 24 h before 72 h of treatment with nutlin-3 RG7388, HDM201, GSK2830371 or combinations. The cells were fixed using Carnoy’s fixative followed by Sulforhodamine B (SRB) assay. |
| Concentrations | 0.2 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | Mice |
| Formulation | 0.5% methylcellulose and 0.1% Tween 80 |
| Dosages | 100 mg/kg |
| Administration | orally |
| Molecular Weight | 555.41 |
| Formula | C26H24Cl2N6O4 |
| CAS Number | 1448867-41-1 |
| Solubility (25°C) | 100 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Mdm2 Products |
|---|
| MMRi64
MMRi64 disrupts Mdm2-MdmX interactions. |
| MeOIstPyrd
MeOIstPyrd is an anti-skin cancer agent. |
| MDM2/XIAP-IN-3
MDM2/XIAP-IN-3 is a dual MDM2/XIAP inhibitor. |
| UNP-6457
UNP-6457 is a potent active MDM2-p53 interaction inhibitor with an IC50 values of 8.9 nM. |
| YL93
YL93 is a dual inhibitors of MDM2/4 with Ki values of 0.64 μM and 1.1 nM for MDM4 and MDM2, respectively. |
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