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

  • J Med Chem. 2015 Aug 27;58(16):6348-58. doi: 10.1021/acs.jmedchem.5b00810.
Philipp Holzer  1 ,  Keiichi Masuya  1 ,  Pascal Furet  1 ,  Joerg Kallen  1 ,  Therese Valat-Stachyra  1 ,  Stéphane Ferretti  1 ,  Joerg Berghausen  1 ,  Michèle Bouisset-Leonard  1 ,  Nicole Buschmann  1 ,  Carole Pissot-Soldermann  1 ,  Caroline Rynn  1 ,  Stephan Ruetz  1 ,  Stefan Stutz  1 ,  Patrick Chène  1 ,  Sébastien Jeay  1 ,  Francois Gessier  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.
PMID: 26181851 DOI: 10.1021/acs.jmedchem.5b00810
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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