5LAZ
Novel Spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) IN COMPLEX WITH COMPOUND BI-0252
Summary for 5LAZ
| Entry DOI | 10.2210/pdb5laz/pdb |
| Descriptor | E3 ubiquitin-protein ligase Mdm2, 4-[(2~{R},3~{a}~{S},5~{S},6~{S},6~{a}~{S})-6'-chloranyl-6-(3-chloranyl-2-fluoranyl-phenyl)-4-(cyclopropylmethyl)-2'-oxidanylidene-spiro[1,2,3,3~{a},6,6~{a}-hexahydropyrrolo[3,2-b]pyrrole-5,3'-1~{H}-indole]-2-yl]benzoic acid, ZINC ION, ... (5 entities in total) |
| Functional Keywords | vienna, ppi, mdm2, hdm2, bi, ligase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 11739.85 |
| 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 Cited by 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: 27775892DOI: 10.1021/acs.jmedchem.6b00900 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.66 Å) |
Structure validation
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