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5xsu
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==novel orally efficacious inhibitors complexed with PARP1== | |
| + | <StructureSection load='5xsu' size='340' side='right' caption='[[5xsu]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5xsu]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XSU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XSU FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8E3:6-fluoranyl-2-(4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)-1~{H}-benzimidazole-4-carboxamide'>8E3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] </span></td></tr> | ||
| + | <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=5xsu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xsu OCA], [http://pdbe.org/5xsu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xsu RCSB], [http://www.ebi.ac.uk/pdbsum/5xsu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xsu ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PARP1_HUMAN PARP1_HUMAN]] Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.<ref>PMID:17177976</ref> <ref>PMID:18172500</ref> <ref>PMID:19344625</ref> <ref>PMID:19661379</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18nM and 42nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway. | ||
| - | + | Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.,Chen X, Huan X, Liu Q, Wang Y, He Q, Tan C, Chen Y, Ding J, Xu Y, Miao Z, Yang C Eur J Med Chem. 2018 Feb 10;145:389-403. doi: 10.1016/j.ejmech.2018.01.018. Epub , 2018 Jan 8. PMID:29335205<ref>PMID:29335205</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Xu, Y | + | <div class="pdbe-citations 5xsu" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Liu, Q]] | ||
| + | [[Category: Xu, Y]] | ||
| + | [[Category: Complex structure]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 05:29, 25 April 2018
novel orally efficacious inhibitors complexed with PARP1
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