6ggn

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'''Unreleased structure'''
 
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The entry 6ggn is ON HOLD until Paper Publication
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==In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor==
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<StructureSection load='6ggn' size='340' side='right' caption='[[6ggn]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6ggn]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GGN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GGN FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EYH:(4~{S})-4-(4-chloranyl-2-methyl-phenyl)-5-(5-chloranyl-2-methyl-phenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-d]imidazol-6-one'>EYH</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ggn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ggn OCA], [http://pdbe.org/6ggn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ggn RCSB], [http://www.ebi.ac.uk/pdbsum/6ggn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ggn ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[http://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.
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== Function ==
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[[http://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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.
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Authors: Kallen, J.
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In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor.,Vaupel A, Holzer P, Ferretti S, Guagnano V, Kallen J, Mah R, Masuya K, Ruetz S, Rynn C, Schlapbach A, Stachyra T, Stutz S, Todorov M, Jeay S, Furet P Bioorg Med Chem Lett. 2018 Aug 26. pii: S0960-894X(18)30703-0. doi:, 10.1016/j.bmcl.2018.08.027. PMID:30217415<ref>PMID:30217415</ref>
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Description: In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6ggn" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: RING-type E3 ubiquitin transferase]]
[[Category: Kallen, J]]
[[Category: Kallen, J]]
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[[Category: Cell cycle]]
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[[Category: Inhibitor complex]]
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[[Category: Ppi with p53]]

Revision as of 08:12, 26 September 2018

In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor

6ggn, resolution 2.00Å

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