Discovery of NVP-CGM097, a highly potent and optimized small molecule inhibitor of Mdm2 under evaluation in a Phase I clinical trial
S Jeay, J Berghausen, N Buschmann, P Chène… - Cancer Research, 2014 - AACR
S Jeay, J Berghausen, N Buschmann, P Chène, R Cozens, D Erdmann, S Ferretti, P Furet…
Cancer Research, 2014•AACRActivation of p53 by blocking the p53-Mdm2 interaction using non-peptidic small-molecule
inhibitors is being pursued as a promising cancer therapeutic strategy. In the present study,
we show the identification of NVP-CGM097, a novel, highly optimized, and selective inhibitor
of the p53-Mdm2 interaction. NVP-CGM097 binds to human Mdm2 protein with a Ki value of
1.3 nM, activates p53 in human cells and induces robust p53-dependent cell cycle arrest
and apoptosis in human p53 wild-type tumor cells. Its activity and selectivity has been tested …
inhibitors is being pursued as a promising cancer therapeutic strategy. In the present study,
we show the identification of NVP-CGM097, a novel, highly optimized, and selective inhibitor
of the p53-Mdm2 interaction. NVP-CGM097 binds to human Mdm2 protein with a Ki value of
1.3 nM, activates p53 in human cells and induces robust p53-dependent cell cycle arrest
and apoptosis in human p53 wild-type tumor cells. Its activity and selectivity has been tested …
Abstract
Activation of p53 by blocking the p53-Mdm2 interaction using non-peptidic small-molecule inhibitors is being pursued as a promising cancer therapeutic strategy. In the present study, we show the identification of NVP-CGM097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. NVP-CGM097 binds to human Mdm2 protein with a Ki value of 1.3 nM, activates p53 in human cells and induces robust p53-dependent cell cycle arrest and apoptosis in human 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. Importantly, NVP-CGM097 displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability, which triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancer. 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-CGM097 in pre-selected patients with p53 wild-type tumors.
Citation Format: Sebastien Jeay, Joerg Berghausen, Nicole Buschmann, Patrick Chène, Robert Cozens, Dirk Erdmann, Stéphane Ferretti, Pascal Furet, Tobias Gabriel, François Gessier, Diana Graus-Porta, Francesco Hofmann, Philipp Holzer, Moriko Ito, Edgar Jacoby, Michael Jensen, Joerg Kallen, Marc Lang, Joanna Lisztwan, Masato Murakami, Carole Pissot-Soldermann, Stephan Ruetz, Caroline Rynn, Dario Sterker, Stefan Stutz, Thérèse Valat, Marion Wiesmann, Keiichi Masuya. Discovery of NVP-CGM097, a highly potent and optimized small molecule inhibitor of Mdm2 under evaluation in a Phase I clinical trial. [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 1797. doi:10.1158/1538-7445.AM2014-1797
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