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

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journal contribution
posted on 27.08.2015, 00:00 authored by Philipp Holzer, Keiichi Masuya, Pascal Furet, Joerg Kallen, Therese Valat-Stachyra, Stéphane Ferretti, Joerg Berghausen, Michèle Bouisset-Leonard, Nicole Buschmann, Carole Pissot-Soldermann, Caroline Rynn, Stephan Ruetz, Stefan Stutz, Patrick Chène, Sébastien Jeay, Francois Gessier
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.