In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor. Issue 20 (1st November 2018)

• Record Type: Journal Article
• Authors: Vaupel, Andrea; Holzer, Philipp; Ferretti, Stephane; Guagnano, Vito; Kallen, Joerg; Mah, Robert; Masuya, Keiichi; Ruetz, Stephan; Rynn, Caroline; Schlapbach, Achim; Stachyra, Thérèse; Stutz, Stefan; Todorov, Milen; Jeay, Sébastien; Furet, Pascal
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 20(2018)
• Page Start: 3404
• Page End: 3408
• Publication Date: 2018-11-01
• Subjects: HDM201 -- Structure guided design -- X-ray structure -- MDM2-p53 protein-protein interaction (PPI) inhibitors -- Pyrrolo[3, 4-d]imidazol-4(1H)- ones; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.08.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Novel rationally designed p53-MDM2 inhibitor scaffold. Structural proof of concept by x-ray crystallography. Optimization of metabolic stability. In vivo proof of concept with high efficacy. Abstract: Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.