Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

• Published in: Journal of medicinal chemistry 2015-08, Vol.58 (16), p.6348-6358
• Main Authors: Holzer, Philipp, Masuya, Keiichi, Furet, Pascal, Kallen, Joerg, Valat-Stachyra, Therese, Ferretti, Stéphane, Berghausen, Joerg, Bouisset-Leonard, Michèle, Buschmann, Nicole, Pissot-Soldermann, Carole, Rynn, Caroline, Ruetz, Stephan, Stutz, Stefan, Chène, Patrick, Jeay, Sébastien, Gessier, Francois
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Drug Discovery; Humans; Isoquinolines - chemical synthesis; Isoquinolines - pharmacokinetics; Isoquinolines - pharmacology; Piperazines - chemical synthesis; Piperazines - pharmacokinetics; Piperazines - pharmacology; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Rats; Structure-Activity Relationship; Tumor Suppressor Protein p53 - genetics; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00810

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.