Small molecule inhibitors of p53/MDM2 interaction.
The discovery of the key negative regulator MDM2 (mouse double minute 2, also termed HDM2 for its human equivalent) provided a great opportunity to manipulate the levels of the tumor suppressor p53 in cancer cells. Activation of p53 in tumor cells by inhibiting the interaction of MDM2 with p53 has therefore been the focus of a large effort in drug discovery. The modulation of protein-protein interactions, however, has historically been very difficult to achieve owing to the large surface area of interaction. In this article, we review the recent accomplishments in this area and our quest for a clinically viable MDM2 inhibitor.
Fotouhi
Nader
N
Discovery Chemistry, Hoffman La-Roche Inc. 340 Kingsland Street, Nutley, NJ 07110, USA. nader.fotouhi@roche.com
Graves
Bradford
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2