Fig. 3: A novel Mdm2 inhibitor, NMI801, efficiently stabilizes p53 in mouse tissues and tumor xenograft models. | Nature Communications

Fig. 3: A novel Mdm2 inhibitor, NMI801, efficiently stabilizes p53 in mouse tissues and tumor xenograft models.

From: p53 dynamics vary between tissues and are linked with radiation sensitivity

Fig. 3

a Chemical structure of NMI801. b X-ray structure of NMI801 bound to the p53-binding pocket of Mdm2, at 2.1 Å resolution. H-bonds are indicated by dashed lines. The Mdm2 sub-pockets binding the p53 residues Leu 26, Trp 23, and Phe 19 are labeled Leu- Trp- and Phe-pocket, respectively. The coordinates have been deposited in the PDB databank (PDB access code = 6I29). c Ki of NMI801 for inhibiting p53-Mdm2 complex formation from a FRET competition assay using Cy5 labeled p53 peptide and full length Mdm2 from Human, Dog, Rat, and Mouse (n = 3 for human, dog; n = 5 for mouse; n = 2 for rat; error bars are SEM; points indicate individual measurements; mean is shown in bar plots). d Quantification of p53 levels by immunofluorescence in HEPA1C1C7 mouse cells 3 h after adding the indicated doses of NMI801 (n = 4 imaging fields; error bars are SEM). e Quantification of p53 levels by immunofluorescence in HEPA1C1C7 mouse cells at the indicated times after adding 0.25, 0.5, or 1 μM NMI801 (n = 4 imaging fields; error bars are SEM). f, g Xenograft tumors of HCT116 were engrafted for 15 days to an average size of ~150 mm3. Mice were then treated with vehicle or NMI801 daily (200 mg/kg). f Tumor volume was measured at the indicated times after NMI801 treatment. g Final tumor volume in p53 wild-type or null mice treated with vehicle or NMI801 (n = 8 mice/condition; error bars are SEM; dots indicate individual data points; *pval = 0.000356, two-sided t-test, no multiple comparison adjustment).

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