title: The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction.
abstract: Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction.
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. pascal.furet@novartis.com
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.forename: Alain
authors.initials: A
authors.lastname: De Pover
authors.forename: Thérèse Stachyra
authors.initials: TS
authors.lastname: Valat
authors.forename: Joanna Hergovich
authors.initials: JH
authors.lastname: Lisztwan
authors.forename: Joerg
authors.initials: J
authors.lastname: Kallen
authors.forename: Keiichi
authors.initials: K
authors.lastname: Masuya
mesh_terms: D008958:Models, Molecular; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014633:Valine / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D014633:Valine