Non peptidic small molecular inhibitors of the p53-MDM2 interaction

Abstract

Cancer is a tumorous disease, which involves the unwanted cell growth and cell division. The imbalance or inactivity of the apoptosis in the body is responsible for the occurrence of tumour and cancer. This apoptosis is regulated by the p53 protein, which is tumour suppressor protein. In the cancer cells, this p53 has been inhibited by the MDM2 protein. MDM2 interact with the p53 and make it inactive. This p53-MDM2 interaction is responsible for the cancer genesis. If we target this interaction, then we can initiate the apoptosis in the cancer cells by making the free p53 protein. There are many strategies to inhibit this p53-MDM2 interaction. Among them non-peptidic small molecule inhibitors are the convenient approach. Small molecule inhibitors have a three pocket binding, so they bind with p53 binding pocket (Trp 23, Leu 26 and Phe 19), present in the MDM2 protein. That is how it spares the p53 protein and makes it available in the cancer cells. Hence, small molecule inhibitors successfully inhibit the p53-MDM2 interaction and can initiate the apoptosis in the cancer cells, which are having the un-mutated p53 protein. They can’t inhibit this interaction in the cells which contains the mutated or deleted p53 protein. Hence, this limitation must be addressed. Many of the small molecular MDM2 inhibitors have been successfully entered into the clinical trials and they are performing well. The clinical data indicate that the small molecular MDM2 inhibitors are having very low toxicity to the normal cells. And they are non-genotoxic so they are near to nontoxic to the normal cells. But none of the any small molecule MDM2 inhibitor has been enters into the market yet. So till then, it has required advancement and research to make more selective and specific for the cancer cells over the normal cells. Keywords: Cancer, Apoptosis, p53 protein, MDM2 protein, p53-MDM2 interaction, Three pocket binding, Small molecule p53-MDM2 interaction inhibitors.