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: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 16 Pg. 6348-58 (Aug 27 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26181851 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Isoquinolines
• NVP-CGM097
• Piperazines
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Clinical Trials, Phase I as Topic
• Drug Discovery
• Humans
• Isoquinolines (chemical synthesis, pharmacokinetics, pharmacology)
• Piperazines (chemical synthesis, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors)
• Rats
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (genetics)
• Xenograft Model Antitumor Assays