title: Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.
abstract: The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.
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
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.
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: 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: Vito
authors.initials: V
authors.lastname: Guagnano
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: Robert
authors.initials: R
authors.lastname: Mah
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stutz
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vaupel
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: Sébastien
authors.initials: S
authors.lastname: Jeay
authors.affiliation: Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Schlapbach
mesh_terms: D018360:Crystallography, X-Ray; D055808:Drug Discovery; D031541:Fluorescence Resonance Energy Transfer; D008968:Molecular Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Anticancer agents; Protein–protein interaction inhibitors; Structure-based design; p53–MDM2 inhibitors