European Journal of Biomedical and Pharmaceutical Sciences

TYPES OF p53/MDM2 INTERACTION INHIBITORS

*Chiragkumar J. Gohil and Malleshappa N. Noolvi

ABSTRACT

p53 protein maintains the normal apoptosis process in body. Override of p53 function, leads to inhibition of apoptosis and occurrence of cancer. Interaction of p53 protein with MDM2 protein is responsible for inhibition of p53 function. Hence to inhibit this interaction is a good strategy for the cancer therapy. This interaction can be inhibited by antagonist of the MDM2 protein. 3 interacting points (i, i+4, i+7) are there on α-helix of p53 protein. And there are 3 main region or pockets present on the MDM2 protein (Trp 23, Leu 26 and Phe 19). Through which p53 binds with MDM2 protein and interact with each other. For the successful design of the MDM2 inhibitors, it should be shows the 3 pocket binding (Trp 23, Leu 26 and Phe 19 pockets of MDM2). Nutlin was the first MDM2 inhibitor. Nutlin class of compounds and many other compounds have been reported till now. There are three main types of MDM2 inhibitors. Types I inhibitors includes the synthetic peptides, which mimics the conformation of p53 helix. Type II inhibitors includes the non-peptide compounds, which have been further subdivided as Non α-helix mimetics (small molecule inhibitors) and α-helix mimetics. Type III inhibitors covers the natural products like Chlorofusin and its analogues. Compounds belong to Type II (a) have been successfully entered into clinical trials. Much efforts and works has been required for the design and discovery of more MDM2 inhibitors. Optimization of the reported compounds is required, so that apart from type II (a), other types of compounds can also be entered into the clinical trials.

Keywords: Cancer, Apoptosis, p53 protein, MDM2 protein, p53/MDM2 interaction inhibitors, types of MDM2 inhibitors, Nutlin.