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 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.|
|Incubation time||72 h|
|Formulation||0.5% methylcellulose and 0.1% Tween 80|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||100 mg/mL in DMSO|
Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma.
Wu CE, et al. Br J Cancer. 2018 Feb 20;118(4):495-508. PMID: 29235570.
Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model.
Chapeau EA, et al. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3151-3156. PMID: 28265066.
|Related Mdm2 Products|
MX69 is a dual inhibitor of MDM2 and XIAP that binds to MDM2 RING protein with binding Kd values of 2.34 μM.
|Cyclic Pifithrin-α hydrobromide
A stable analog of Pifithrin-α (Product Code P4359) with similar biological activities and lower cellular toxicity.
Puromycin aminonucleoside is the aminonucleoside portion of the antibiotic puromycin, and a puromycin analog which does not inhibit protein synthesis or induce apoptosis.
Idasanutlin (RG-7388) is a potent and selective p53-MDM2 inhibitor with IC50 of 6 nM showing improved in vitro binding as well as cellular potency/selectivity.
MI-773 is an orally available MDM2 antagonist with Ki of 0.88 nM.
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