title: Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.
abstract: Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Gessier
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Kallen
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Edgar
authors.initials: E
authors.lastname: Jacoby
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Stachyra-Valat
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruetz
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jeay
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Holzer
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Masuya
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland. Electronic address: pascal.furet@novartis.com.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007546:Isoquinolines; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; Protein–protein interaction inhibitors; p53