Approaches to the Discovery of Small-molecule MDM2-p53 Inhibitors
Conference Recording May 28, 2013
About the SpeakerIan Hardcastle gained his PhD in Synthetic Organic Chemistry in 1990 at Manchester University. From there he joined Prof. M Jarman’s team as a post-doctoral fellow at The Institute of Cancer Research, Sutton working on the medicinal chemistry of antiestrogens, CYP17A1 inhibitors including the discovery of abiraterone, and signalling targets in cancer. In 1999 he joined the CR UK funded drug discovery team at Newcastle University as Lecturer in Medicinal Chemistry.
The p53 tumour suppressor plays a pivotal role in the cell by reacting to stress. Activation of p53 protein results in the transcription of a number of genes that govern progression through the cell cycle, the initiation of DNA repair, and apoptosis. The activity of p53 is tightly regulated by the MDM2 protein, which itself is transcribed in response to p53 activation. MDM2 binds to and inactivates p53 and also ubiquitylates the MDM2-p53 complex to target it for proteosomal degradation. In normal cells the balance between active p53 and inactive MDM2-bound p53 is maintained in a negative feedback loop. Inhibition of the MDM2-p53 protein-protein complex by small molecule inhibitors is expected to reactivate normal p53 pathways in cells overexpressing MDM2, consequently exerting an anti-cancer effect. The MDM2-p53 binding interaction has many attractive features for small-molecule inhibition, as it consists of a relatively deep binding groove on the surface of the MDM2 protein into which an amphipathic helix of p53 binds. The X-ray crystal structures of MDM2 with a number of peptide and small-molecule ligands bound have been reported, demonstrating the prevalent key shape-filling and hydrophobic interactions. Potent MDM2-p53 inhibitors, such as Nutlin-3 and the spirooxindoles have demonstrated cellular activity consistent with inhibition of MDM2-p53 binding and have shown in vivo antitumor activity. We have developed inhibitors of the MDM2-p53 interaction. The first series of inhibitors, based on an isoindolinone scaffold, was developed using in silico screening and combinatorial synthesis. NMR structural studies with key inhibitors suggested further variations around the isoindolinone scaffold. SAR studies yielded compounds with nanomolar potency, comparable to published competitors. The use of screening to discover pyrrole-based MDM2-p53 inhibitors will also be described.