Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors
Philipp Holzer(Novartis Institutes for BioMedical Research), Keiichi Masuya(Novartis Institutes for BioMedical Research), Pascal Furet(Novartis (Switzerland)), Joerg Kallen(Novartis Institutes for BioMedical Research), Therese‐Marie Stachyra(Novartis (Switzerland)), Stéphane Ferretti(Novartis (Switzerland)), Joerg Berghausen(Novartis Institutes for BioMedical Research), Michèle Bouisset-Leonard(Novartis Institutes for BioMedical Research), Nicole Buschmann(Novartis Institutes for BioMedical Research), Carole Pissot‐Soldermann(Novartis (Switzerland)), Caroline Rynn(Novartis (Switzerland)), Stephan Ruetz(Novartis (Switzerland)), Stefan Stutz(Novartis Institutes for BioMedical Research), Patrick Chêne(Novartis Institutes for BioMedical Research), Sébastien Jeay(Novartis (Switzerland)), F. Gessier(Novartis (Switzerland))
Cited by 206Open Access
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.
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