Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument

被引：59

作者：

Furet, Pascal ^{[1
]}

Masuya, Keiichi ^{[1
]}

Kallen, Joerg ^{[1
]}

Stachyra-Valat, Therese ^{[1
]}

Ruetz, Stephan ^{[1
]}

Guagnano, Vito ^{[1
]}

Holzer, Philipp ^{[1
]}

Mah, Robert ^{[1
]}

Stutz, Stefan ^{[1
]}

Vaupel, Andrea ^{[1
]}

Chene, Patrick ^{[1
]}

Jeay, Sebastien ^{[1
]}

Schlapbach, Achim ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, WKL 136-P-12, CH-4002 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 19期

关键词：

p53-MDM2; inhibitors; Protein-protein interaction inhibitors; Anticancer agents; Structure-based design; SMALL-MOLECULE INHIBITORS; CLINICAL-TRIALS; MDM2; P53;

D O I：

10.1016/j.bmcl.2016.08.010

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyra-zolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4837 / 4841

页数：5

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