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

Furet, Pascal and Masuya, Keiichi and Kallen, Joerg and Valat, Therese-Marie and Guagnano, Vito and Holzer, Philipp and Mah, Robert and Stutz, Stefan and Vaupel, Andrea and Chene, Patrick and Jeay, Sebastien and Ruetz, Stephan and Schlapbach, Achim (2016) Discovery of a novel class of highly potent inhibitors of the p53–MDM2 interaction by structure-based design starting from a conformational argument. Bioorganic and Medicinal Chemistry Letters, 26 (19). pp. 4837-4841. ISSN 1464-3405

Abstract

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 pyrazolopyrrolidinone 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.

Item Type: Article
Keywords: Anticancer agents p53–MDM2 inhibitors Protein–protein interaction inhibitors Structure-based design
Date Deposited: 14 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/29505

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