REVIEW OF DESIGN APPROACHES AND CLINICAL PROGRESS OF MDM2 INHIBITORS

Abstract

Activation of the oncogenes and inhibition of the apoptotic function of the p53 protein is a gateway for the cancer genesis. Interaction of the MDM2 protein with p53 protein is responsible for the inhibition of the p53 function. Inhibiting the p53-MDM2 interaction by drug will lead to the p53 release in the cancer cells. And can restart the apoptosis in the cancer cell. Computational methods successfully used for the design and development of the new, potent MDM2 inhibitors. Researchers and pharma companies used rational approach like target-based drug design or ligand-based drug design to develop the novel MDM2 inhibitors. The number of MDM2 inhibitors, has been designed by the computer-aided drug design and in-silico studies. In clinical studies, MDM2 inhibitors are led by RG7112. RG7112 completed its phase-1 trials in 2016, and recently it is under phase-2 trials. Along with RG7112, the number of potent MDM2 inhibitors entered the clinical trials successfully. It indicates the successful development of this class (MDM2 inhibitors). MDM2 inhibitors were found very effective in various studies for the treatment of various kinds of cancers. They have good selectivity for the tumor cells over the normal cells. It induced the dose dependent cell cycle arrest only; in the normal cells. In studies, MDM2 inhibitors successfully detached the p53 protein from the MDM2 protein. And restart the cell-killing function of the p53 protein in the cancer cells. Hence, MDM2 inhibitors can selectively kill the cancer cells over the normal cells.