In vitro: MI-773 binds to MDM2 with Ki of 0.88 nM. MI-773 potently inhibits cell growth in cancer cell lines, including SJSA-1 (IC50, 0.092 μM), RS4;11 (IC50, 0.089 μM), LNCaP (IC50, 0.27 μM), and HCT-116 (IC50, 0.20 μM) cells, and displays high selectivity over cancer cell lines with mutated or deleted p53, including SAOS-2 (IC50, >10 μM), PC-3 (IC50, >10 μM), SW620 (IC50, >10 μM), and HCT-116 (p53-/-) (IC50, >20 μM) cells. In vivo: In the SJSA-1 osteosarcoma, acute lymphoblastic leukemia RS4;11, LNCaP prostate cancer, and HCT-116 colon cancer xenograft model, MI-773 (p.o.) effectively inhibits tumor growth in a dose-dependent manner (10 mg/kg, 30 mg/kg, 50 mg/kg, 100 mg/kg, and 200 mg/kg,).
|Cell lines||SJSA-1, RS4;11, LNCaP, SAOS-2, PC-3, SW620, HCT-116, and HCT-116 (p53-/-) cells|
|Preparation method||Cell growth inhibition activity is determined in a water-soluble tetrazolium-based assay. Cell death is measured by trypan blue staining and apoptosis is determined using an Annexin V-FLUOS staining kit.|
|Incubation time||~48 h|
|Animal models||SCID mice with SJSA-1 osteosarcoma (females), acute lymphoblastic leukemia RS4;11 (females), LNCaP prostate cancer (males), or HCT-116 colon cancer (females) xenograft model|
|Formulation||10% PEG400: 3% Cremophor: 87% PBS, or 2% TPGS: 98% PEG200|
|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|
Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma.
Lu J, et al. Oncotarget. 2016 Dec 13;7(50):82757-82769. PMID: 27764791.
Therapeutic Inhibition of the MDM2-p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas.
Nör F, et al. Clin Cancer Res. 2017 Feb 15;23(4):1036-1048. PMID: 27550999.
SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression.
Wang S, et al. Cancer Res. 2014 Oct 15;74(20):5855-65. PMID: 25145672.
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SL-01 is a p53-Mdm2 interaction inhibitor with IC50 of 3.18 μM.
Nutlin-3b is a p53/MDM2 antagonist or inhibitor with IC50 value of 13.6 μM, 150-fold less potent (+)-enantiomer of Nutlin-3 as in comparison with opposite enantiomer Nutlin-3a.
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