4ZYC

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode: Hdm2 (MDM2) complexed with cpd5

Summary for 4ZYC

• Entry DOI: 10.2210/pdb4zyc/pdb
• Related: 4DIJ 4OQ3
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (S)-2-(2-((2H-tetrazol-5-yl)methoxy)-4-methylphenyl)-1-(4-chlorophenyl)-6,7-diethoxy-1,2-dihydroisoquinolin-3(4H)-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ppi with p53, inhibitor complex, ligase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 3
• Total formula weight: 35214.11

Authors

Kallen, J. (deposition date: 2015-05-21, release date: 2015-07-22, Last modification date: 2024-01-10)

Primary citation

Gessier, F.,Kallen, J.,Jacoby, E.,Chene, P.,Stachyra-Valat, T.,Ruetz, S.,Jeay, S.,Holzer, P.,Masuya, K.,Furet, P.
Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.
Bioorg.Med.Chem.Lett., 25:3621-3625, 2015

PubMed Abstract: Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.

PubMed: 26141769
DOI: 10.1016/j.bmcl.2015.06.058

Experimental method

X-RAY DIFFRACTION (1.95 Å)