An effective strategy to restore p53 activity in cancer cells containing wild type p53 is to inhibit the Mdm2-p53 protein-protein interaction (PPI). NVP-CGM097 is a novel PPI inhibitor under evaluation in a Phase I clinical trial. It binds to the p53 binding-site of the Mdm2 protein, disrupting the interaction between both proteins, leading to an activation of the p53 pathway.

The main biophysical and biochemical inhibitory characteristics of NVP-CGM097 are presented here. These include an affinity constant for Mdm2 in the nanomolar range and a selectivity of 3 orders of magnitude vs. Mdm4. The binding kinetics of NVP-CGM097 to Mdm2 are characterized by a high association rate constant (Kon =37 x 106 M-1.s-1) and a moderate dissociation rate constant (Koff =0.071 s-1). Additionally, NVP-CGM097 exhibits an 8-fold greater affinity for Mdm2 over Nutlin-3 due to a longer residence time of the Mdm2-inhibitor complex.

Moreover, biochemical studies have revealed the species specificity of NVP-CGM097 with human Mdm2 being inhibited more strongly than the dog, mouse or rat forms of the protein. This was confirmed in cellular assays where NVP-CGM097 treatment resulted in induction of p53 target gene expression (p21, PUMA and Mdm2) only in human, but not in dog, mouse or rat cell lines.

Citation Format: Thérèse Valat, Keiichi Masuya, Frédéric Baysang, Geneviève Albrecht, Nicole Buschmann, Dirk Erdmann, Pascal Furet, Tobias Gabriel, François Gessier, Francesco Hofmann, Philipp Holzer, Joerg Kallen, Carole Pissot-Solderman, Stefan Stutz, Patrick Chène, Sébastien Jeay. Mechanistic study of NVP-CGM097: a potent, selective and species specific inhibitor of p53-Mdm2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1798. doi:10.1158/1538-7445.AM2014-1798

©2014 American Association for Cancer Research.
2014