Nutlin-3 is a small molecule inhibitor of the MDM2/p53 interaction, which leads to the non-genotoxic p53 stabilization, activation of cell cycle arrest and apoptosis pathways. Nutlin-3 inhibits the MDM2-p53 interaction with IC50 of 0.09 μM and synergistically activates p53 to suppress tumor growth. Nutlin-3 induces apoptosis in cancer cells. Nutlin-3 treatment induces the expression of MDM2 and p21, and displays potent antiproliferative activity with IC50 of ~1.5 μM in cells with wild-type p53 such as HCT116, RKO and SJSA-1. Nutlin-3 is currently in phase I clinical trial for the treatment of retinoblastoma.
|Cell lines||wild-type p53 (HCT116, RKO, and SJSA-1) and mutant p53 (MDA-MB-435 and SW480) cell lines|
|Preparation method||Effect of the enantiomers of Nutlin-3 on the growth and viability of cancer cells with wild-type p53 (HCT116, RKO, and SJSA-1) and mutant p53 (MDA-MB-435 and SW480). Cells were grown, treated, and analyzedAntiproliferative and cytotoxic activity of Nutlin-1. Exponentially growing cancer cells with wild-type p53 (HCT116, RKO, and SJSA-1) or mutant p53 (MDA-MB-435 and SW480) were incubated with a range of concentrations for 5 days and the cell mass and viability were measured by the MTT assay.|
|Incubation time||5 days|
|Animal models||Nude mice bearing subcutaneous human cancer xenografts|
|Formulation||2% Klucel, 0.5% Tween 80|
|Dosages||200 mg/kg twice daily for 3 weeks|
|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||DMSO 100 mg/mL|
Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth.
Zhang Y, et al. Cancer Biol Ther. 2012 Aug;13(10):915-24. PMID: 22785205.
Recent advances in the therapeutic perspectives of Nutlin-3.
Secchiero P, et al. Curr Pharm Des. 2011;17(6):569-77. PMID: 21391907.
Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1alpha and Hdm2.
LaRusch GA, et al. Cancer Res. 2007 Jan 15;67(2):450-4. PMID: 17234751.
|Related Mdm2 Products|
MI-773 is an orally available MDM2 antagonist with Ki of 0.88 nM.
Kevetrin hydrochloride is a small molecule and activator of the tumor suppressor protein p53, with potential antineoplastic activity.
RG7112 is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2.
NSC 207895 suppresses MDMX with IC50 of 2.5 μM, leading to enhanced p53 stabilization/activation and DNA damage, and also regulates MDM2, an E3 ligase.
SL-01 is a p53-Mdm2 interaction inhibitor with IC50 of 3.18 μM.
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