5LAV

Novel Spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) in complex with compound 6b

Summary for 5LAV

• Entry DOI: 10.2210/pdb5lav/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (3~{S},3'~{S},4'~{S})-4'-azanyl-6-chloranyl-3'-(3-chlorophenyl)-1'-(2,2-dimethylpropyl)spiro[1~{H}-indole-3,2'-pyrrolidine]-2-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: vienna, ppi, mdm2, hdm2, bi, ligase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 1
• Total formula weight: 11398.22

Authors

Kessler, D.,Gollner, A. (deposition date: 2016-06-15, release date: 2016-11-02, Last modification date: 2024-05-08)

Primary citation

Gollner, A.,Rudolph, D.,Arnhof, H.,Bauer, M.,Blake, S.M.,Boehmelt, G.,Cockroft, X.L.,Dahmann, G.,Ettmayer, P.,Gerstberger, T.,Karolyi-Oezguer, J.,Kessler, D.,Kofink, C.,Ramharter, J.,Rinnenthal, J.,Savchenko, A.,Schnitzer, R.,Weinstabl, H.,Weyer-Czernilofsky, U.,Wunberg, T.,McConnell, D.B.
Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction.
J. Med. Chem., 59:10147-10162, 2016

PubMed Abstract: Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI-0252).

PubMed: 27775892
DOI: 10.1021/acs.jmedchem.6b00900

Experimental method

X-RAY DIFFRACTION (1.73 Å)