1. The Initial Evaluation Of MDM2 Inhibitors Based On P53-MDM2 Complex Crystal Structure 2. Chromosome Locus Of ATRA-induced Gene RA109, Intracellular Localization And Prokaryotic Expression Of RA109 Protein

In normal cells, the wild-type (wt) p53 protein is present at a very low concentration. However, in response to various stimuli, it accumulates and induces cell-cycle arrest and/or apoptosis. One of the mechanisms by which p53 is inactivated is the autoregulatory feedback loop of MDM2 and p53. In this loop, p53 stimulates the expression of MDM2 and the newly expressed MDM2 protein inhibits the transcriptional activity of p53 because it binds to its transactivation domain. An additional mechanism by which MDM2 regulates p53 protein is p53 degradation mediated by MDM2. The disruption of the interaction between the two proteins is therefore an attractive therapeutic target for treatment of the subset of human cancers in which the above pathway is active. All tumor cells expressing the wt p53 protein could therefore be targeted by this approach, assuming that they have a functional p53 pathway. The feasibility of this strategy has been demonstrated by invention of some peptidic MDM2 inhibitors. However, these peptides were inserted into the thioredoxin protein or fused to the GST, so apart from the fact that they have inhibitory proprties owing the presence of the fused peptide, these fusion proteins can create steric clashes that enhance the effect of the peptide. Recently one study group has shown that an octamer synthetic peptide, which potently inhibits the p53-MDM2 interaction in vitro, stimulates the p53 pathway in tumor cells that express wt p53. As it is expensive to synthesize peptides, it remains to be established whether non-peptidic small molecules can inhibit the p53-hdm2 interaction in a cellular...