Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.

Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

Comparison of translabial ultrasonographic and urodynamic data of female patients with urinary incontinence: Importance of translabial ultrasonography in the diagnosis of incontinence.

OBJECTIVE: To explore the diagnostic importance of translabial ultrasonographic data in incontinence, for comparison with urodynamic data. MATERIAL AND METHODS: The study was performed between January and May 2017 on 64 patients aged between 40 and 65 years with complaints of mixed type incontinence. The patients were separated into two groups according to their urodynamic data. Translabial ultrasonography was performed in both groups. RESULTS: Mean age of the patients was 51.19±7.01 years, and mean body mass index was 26.69±2.02 kg/m2. The patients were separated into two groups as those with (n=33) or without (n=31) stress urinary incontinence based on urodynamic findings (despite the presence of mixed urinary incontinence complaints, stress urinary incontinence and detrusor overactivity associated with incontinence could not be detected in the urodynamic study). Average x descend, y descend and bladder neck mobilization values detected with translabial ultrasonography were found to be statistically significantly higher in the urodynamic stress incontinence group. There was an opposite-directional, 37.6% and statistically significant relation between maximum cystometric capacity and x descend parameters. Y descend values and bladder neck mobilization of females with negative Q-tip test were found to be statistically significantly lower than females with positive Q-tip test. CONCLUSION: As a complementary examination tool in the evaluation of urinary incontinence translabial ultrasonography may become one of the main diagnostic evaluation tools in the future.

The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant.

The p53-binding site of MDM2 holds great promise as a target for therapeutic intervention in MDM2-amplified p53 wild-type forms of cancer. Despite the extensive validation of this strategy, there are relatively few crystallographically determined co-complex structures for small-molecular inhibitors of the MDM2-p53 interaction available in the PDB. Here, a surface-entropy reduction mutant of the N-terminal domain of MDM2 that has been designed to enhance crystallogenesis is presented. This mutant has been validated by comparative ligand-binding studies using differential scanning fluorimetry and fluorescence polarization anisotropy and by cocrystallization with a peptide derived from p53. Using this mutant, the cocrystal structure of MDM2 with the benchmark inhibitor Nutlin-3a has been determined, revealing subtle differences from the previously described co-complex of MDM2 with Nutlin-2.