title: Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.
abstract: As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Holzer
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Masuya
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Kallen
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Therese
authors.initials: T
authors.lastname: Valat-Stachyra
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ferretti
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Berghausen
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Michèle
authors.initials: M
authors.lastname: Bouisset-Leonard
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Buschmann
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Pissot-Soldermann
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rynn
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruetz
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stutz
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jeay
authors.affiliation: Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Gessier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D055808:Drug Discovery; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; C000602644:NVP-CGM097; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2