PDBsum entry 4zyc

Ligase

PDB id: 4zyc

Contents

Protein chains

84 a.a.

Ligands

4SS ×3

SO4

Waters ×104

References listed in PDB file

Key reference

• Title: Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-Mdm2 interaction with a distinct binding mode.
• Authors: F.Gessier, J.Kallen, E.Jacoby, P.Chène, T.Stachyra-Valat, S.Ruetz, S.Jeay, P.Holzer, K.Masuya, P.Furet.
• Ref.: Bioorg Med Chem Lett, 2015, 25, 3621-3625. [DOI no: 10.1016/j.bmcl.2015.06.058]
• PubMed id: 26141769

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.