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

被引：171

作者：

Holzer, Philipp ^{[1
]}

Masuya, Keiichi ^{[1
]}

Furet, Pascal ^{[1
]}

Kallen, Joerg ^{[1
]}

Valat-Stachyra, Therese ^{[1
]}

Ferretti, Stephane ^{[1
]}

Berghausen, Joerg ^{[1
]}

Bouisset-Leonard, Michele ^{[1
]}

Buschmann, Nicole ^{[1
]}

Pissot-Soldermann, Carole ^{[1
]}

Rynn, Caroline ^{[1
]}

Ruetz, Stephan ^{[1
]}

Stutz, Stefan ^{[1
]}

Chene, Patrick ^{[1
]}

Jeay, Sebastien ^{[1
]}

Gessier, Francois ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 16期

关键词：

P53-MDM2; INTERACTION; ANTAGONISTS; PATHWAY;

D O I：

10.1021/acs.jmedchem.5b00810

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

引用

页码：6348 / 6358

页数：11

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