MI-773 (SAR405838 (MI 773)) is an orally available MDM2 antagonist with Ki of 0.88 nM. Phase 1.

MDM2:0.88 nM(Ki)

SAR405838 binds to MDM2 with Ki of 0.88 nM. SAR405838 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. [1]

In the SJSA-1 osteosarcoma, acute lymphoblastic leukemia RS4;11, LNCaP prostate cancer, and HCT-116 colon cancer xenograft model, SAR405838 (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]

Fluorescence-polarization binding assay: Binding af?nities of MDM2 inhibitors and p53 peptide to MDM2 protein are determined using an Fluorescence-polarization (FP) binding assay. Binding af?nities of MI-773 to Bcl-2, Bcl-xL, Mcl-1, and β-catenin are determined using a competitive FP-based assay, and its binding af?nity to MDMx is determined using Biolayer Interferometry technology.

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.(Only for Reference)