MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 
as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding 
that can reactivate p53 in cancer cells may offer an effective approach for 
cancer therapy. RG7112 is a potent and selective member of the nutlin family of 
MDM2 antagonists currently in phase I clinical studies. RG7112 binds MDM2 with 
high affinity (K(D) ~ 11 nmol/L), blocking its interactions with p53 in vitro. A 
crystal structure of the RG7112-MDM2 complex revealed that the small molecule 
binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 
amino acid residues. Treatment of cancer cells expressing wild-type p53 with 
RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. 
RG7112 showed potent antitumor activity against a panel of solid tumor cell 
lines. However, its apoptotic activity varied widely with the best response 
observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, 
inhibition of caspase activity did not change the kinetics of p53-induced cell 
death. Oral administration of RG7112 to human xenograft-bearing mice at nontoxic 
concentrations caused dose-dependent changes in proliferation/apoptosis 
biomarkers as well as tumor inhibition and regression. Notably, RG7112 was 
highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our 
findings offer a preclinical proof-of-concept that RG7112 is effective in 
treatment of solid tumors expressing wild-type p53.