Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been 
considered an attractive approach for cancer treatment. However, the hydrophobic 
protein-protein interaction surface represents a significant challenge for the 
development of small-molecule inhibitors with desirable pharmacological 
profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical 
development. Here, we report the discovery and characterization of a second 
generation clinical MDM2 inhibitor, RG7388, with superior potency and 
selectivity.