Joerg Berghausen

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides

Recently, a variety of studies concerned with the permeability and oral bioavailability of cyclic peptides have been reported. In particular, strategies aiming at modifying peptides to maintain or to enhance solubility while enabling permeability constitute a significant challenge, but are of high interest to ensure a smooth drug discovery process. Current methodologies include N-methylation, matching of hydrogen bonding acceptors and donors across the macrocycle, and additional masking of polarity. In this study, we investigate further the pivotal effects of shielding on permeability and studied the metabolism of the corresponding peptides in more detail by comparing peptide concentrations in the portal versus the jugular vein in rats. Interestingly, minor changes in one particular side chain impacts both permeability and liver metabolism.Graphical Abstract

Abstract 1797: Discovery of NVP-CGM097, a highly potent and optimized small molecule inhibitor of Mdm2 under evaluation in a Phase I clinical trial

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 Chene, Robert Cozens, Dirk Erdmann, Stephane Ferretti, Pascal Furet, Tobias Gabriel, Francois 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, Therese 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

Abstract DDT01-01: Discovery of CGM097 as a novel Mdm2 inhibitor

The antiproliferative transcriptional activity of the p53 tumor suppressor is inhibited by the binding of its transactivation domain to the regulator protein Mdm2. Overexpression of Mdm2 or amplification of its gene, leading to a loss of p53 function, has been observed in various tumors. An attractive approach to restore p53 activity in such tumors and to inhibit their growth is to prevent the association of the two proteins by blocking the p53 binding pocket of Mdm2 with a small molecule. In this presentation, we report how the starting point of CGM097 was discovered and how innovative medicinal chemistry efforts led to further optimization of the potency and physico-chemical properties, resulting in CGM097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. Citation Format: Keiichi Masuya, Pascal Furet, Stefan Stutz, Philipp Holzer, Carole Pissot-Soldmann, Nicole Buschmann, Therese Valat, Stephane Ferretti, Stephan Ruetz, Caroline Rynn, Joerg Berghausen, Edgar Jacoby, Marc Lang, Tobias Gabriel, Francesco Hofmann, Joerg Kallen, Sebastien Jeay, Francois Gessier. Discovery of CGM097 as a novel Mdm2 inhibitor. [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 DDT01-01. doi:10.1158/1538-7445.AM2014-DDT01-01