7BJ6

Inhibitor of MDM2-p53 Interaction

Summary for 7BJ6

• Entry DOI: 10.2210/pdb7bj6/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, DIMETHYL SULFOXIDE, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: ligase, cell cycle, apoptosis, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 12216.97

Authors

Williams, P.A. (deposition date: 2021-01-14, release date: 2021-04-07, Last modification date: 2024-05-15)

Primary citation

Chessari, G.,Hardcastle, I.R.,Ahn, J.S.,Anil, B.,Anscombe, E.,Bawn, R.H.,Bevan, L.D.,Blackburn, T.J.,Buck, I.,Cano, C.,Carbain, B.,Castro, J.,Cons, B.,Cully, S.J.,Endicott, J.A.,Fazal, L.,Golding, B.T.,Griffin, R.J.,Haggerty, K.,Harnor, S.J.,Hearn, K.,Hobson, S.,Holvey, R.S.,Howard, S.,Jennings, C.E.,Johnson, C.N.,Lunec, J.,Miller, D.C.,Newell, D.R.,Noble, M.E.M.,Reeks, J.,Revill, C.H.,Riedinger, C.,St Denis, J.D.,Tamanini, E.,Thomas, H.,Thompson, N.T.,Vinkovic, M.,Wedge, S.R.,Williams, P.A.,Wilsher, N.E.,Zhang, B.,Zhao, Y.
Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.
J.Med.Chem., 64:4071-4088, 2021

PubMed Abstract: Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent and inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

PubMed: 33761253
DOI: 10.1021/acs.jmedchem.0c02188

Experimental method

X-RAY DIFFRACTION (1.59 Å)