View source for 5lav


==Novel Spiro[3H-indole-3,2 -pyrrolidin]-2(1H)-one Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) in complex with compound 6b==
<StructureSection load='5lav' size='340' side='right'caption='[[5lav]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lav]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LAV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LAV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.73&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6SK:(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'>6SK</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5lav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lav OCA], [https://pdbe.org/5lav PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lav RCSB], [https://www.ebi.ac.uk/pdbsum/5lav PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lav ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.
== Function ==
[https://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref> 
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== Publication Abstract from PubMed ==
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'-(cyclopropylme thyl)-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).

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.,Gollner A, Rudolph D, Arnhof H, Bauer M, Blake SM, Boehmelt G, Cockcroft XL, 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 DB J Med Chem. 2016 Oct 24. PMID:27775892<ref>PMID:27775892</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5lav" style="background-color:#fffaf0;"></div>

==See Also==
*[[MDM2 3D structures|MDM2 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gollner A]]
[[Category: Kessler D]]