Stabilization of p53 protein by preventing its interaction with the negative regulator Mdm2 leads to selective induction of the p53 pathway, thus offering a promising cancer therapeutic strategy in p53 wild-type tumors. In the present study, we show the identification of NVP-HDM201, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. NVP-HDM201 activates p53 in human cells and induces robust p53-dependent cell cycle arrest and apoptosis, selectively in p53 wild-type tumor cells. Its activity and selectivity has been tested and confirmed across a large panel of cancer cell lines from the Cancer Cell Line Encyclopedia. In vivo, NVP-HDM201 shows a dose-proportional pharmacokinetic (PK) profile and a clear PK/PD relationship, resulting in tumor growth inhibition and regression in SJSA-1 tumor-bearing rats at well-tolerated oral (p.o.) doses. The validation and understanding of its mechanism of action, the overall favorable drug-like properties and the characterization of its on-target toxicological profile in preclinical species strongly supported the initiation of Phase I clinical trials with NVP-HDM201 in pre-selected patients with p53 wild-type tumors.

Citation Format: Sébastien Jeay, Patrick Chène, Stéphane Ferretti, Pascal Furet, Bjoern Gruenenfelder, Vito Guagnano, Nelson Guerreiro, Ensar Halilovic, Francesco Hofmann, Joerg Kallen, Michelle Léonard, Robert Mah, Keiichi Masuya, Rita Ramos, Caroline Rynn, Stephan Ruetz, Thérèse Stachyra-Valat, Stefan Stutz, Andrea Vaupel, Jens Wuerthner, Philipp Holzer. NVP-HDM201: cellular and in vivo profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1225.