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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

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. Thi...

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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
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creator	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
description	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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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
title	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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