4ZYF

Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with NVP-CGM097

Summary for 4ZYF

• Entry DOI: 10.2210/pdb4zyf/pdb
• Related: 4DIJ 4OQ3 4ZYC
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: ppi with p53, inhibitor complex, cell cycle
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 1
• Total formula weight: 11850.76

Authors

Kallen, J. (deposition date: 2015-05-21, release date: 2015-07-29, Last modification date: 2024-01-10)

Primary citation

Holzer, P.,Masuya, K.,Furet, P.,Kallen, J.,Valat-Stachyra, T.,Ferretti, S.,Berghausen, J.,Bouisset-Leonard, M.,Buschmann, N.,Pissot-Soldermann, C.,Rynn, C.,Ruetz, S.,Stutz, S.,Chene, P.,Jeay, S.,Gessier, F.
Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.
J.Med.Chem., 58:6348-6358, 2015

PubMed Abstract: 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.

PubMed: 26181851
DOI: 10.1021/acs.jmedchem.5b00810

Experimental method

X-RAY DIFFRACTION (1.8 Å)