| Identification | Back Directory | [Name]
SAR405838 (MI-773) | [CAS]
1303607-60-4 | [Synonyms]
MI 77301
SAR405838
SAR405838 (MI-773)
MI-773 (SAR405838)
SAR405838, MI-77301
MI-77301 (SAR405838)
SAR405838 (MI-773) USP/EP/BP
SAR405838;SAR-405838;SAR 405838
MI-773 (2'S,3R isomer, SAR-405838)
(2'S,3R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-1,2-dihydro-N-(trans-4-hydroxycyclohexyl)-2-oxo-spiro[3H-indole-3,3'-pyrrolidine]-5'-carboxamide
Spiro[3H-indole-3,3'-pyrrolidine]-5'-carboxamide, 6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-1,2-dihydro-N-(trans-4-hydroxycyclohexyl)-2-oxo-, (2'S,3R,4'S,5'R)- | [Molecular Formula]
C29H34Cl2FN3O3 | [MDL Number]
MFCD28976052 | [MOL File]
1303607-60-4.mol | [Molecular Weight]
562.5 |
| Chemical Properties | Back Directory | [Boiling point ]
732.1±60.0 °C(Predicted) | [density ]
1.36±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
≥17.2 mg/mL in DMSO | [form ]
Powder | [pka]
12.03±0.70(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Description]
The protein p53, often called the ‘guardian of the genome,’ is a transcription factor that is activated in response to cellular stress (low oxygen levels, heat shock, DNA damage, etc.) and acts to prevent further proliferation of the stressed cell by promoting cell cycle arrest or apoptosis. Its role as a tumor suppressor is evident by the observation that approximately 50% of human tumors have mutated or non-functional p53. Mdm2, a key negative regulator of p53, which is over-expressed in many human tumors, functions by binding to and targeting p53 for proteasomal degradation. MI-77301 binds to MDM2 with a Ki value of 0.88 nM and blocks the MDM2-p53 interaction. It activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell cycle arrest and/or apoptosis. In an SJSA-1 xenograft model of osteosarcoma, a single dose of 200 mg/kg MI-77301 induces complete tumor regression in mice by upregulating the pro-apoptotic protein PUMA. | [Uses]
MI-773 is aninhibitors of MDM2-p53 protein-protein interaction (MDM2 inhibitors), currently investigated in clinical trials for cancer treatment. | [in vivo]
At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. 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,)[1].
| [References]
[1]. wang s, sun w, zhao y, et al. sar405838: an optimized inhibitor of mdm2-p53 interaction that induces complete and durable tumor regression. cancer res, 2014, 74(20): 5855-5865. |
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