5LN2

Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument

Summary for 5LN2

• Entry DOI: 10.2210/pdb5ln2/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (4~{S})-5-[5-chloranyl-2-[2-(dimethylamino)ethoxy]phenyl]-4-(4-chloranyl-2-methyl-phenyl)-2-(2-methoxyphenyl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-c]pyrazol-6-one, SULFATE ION, ... (5 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: 11881.11

Authors

Kallen, J. (deposition date: 2016-08-02, release date: 2016-09-07, Last modification date: 2024-01-10)

Primary citation

Furet, P.,Masuya, K.,Kallen, J.,Stachyra-Valat, T.,Ruetz, S.,Guagnano, V.,Holzer, P.,Mah, R.,Stutz, S.,Vaupel, A.,Chene, P.,Jeay, S.,Schlapbach, A.
Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.
Bioorg.Med.Chem.Lett., 26:4837-4841, 2016

PubMed Abstract: The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.

PubMed: 27542305
DOI: 10.1016/j.bmcl.2016.08.010

Experimental method

X-RAY DIFFRACTION (1.58 Å)