6w35
From Proteopedia
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==A new Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry== | ==A new Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry== | ||
| - | <StructureSection load='6w35' size='340' side='right'caption='[[6w35]]' scene=''> | + | <StructureSection load='6w35' size='340' side='right'caption='[[6w35]], [[Resolution|resolution]] 1.98Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W35 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W35 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6w35]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Chimpansee_troglodytes Chimpansee troglodytes]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W35 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W35 FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w35 OCA], [http://pdbe.org/6w35 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w35 RCSB], [http://www.ebi.ac.uk/pdbsum/6w35 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w35 ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=SKV:2-fluoranyl-~{N}-[(2~{R})-1-[1-(2~{H}-indazol-5-yl)-3-methyl-2,4-bis(oxidanylidene)-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxidanylidene-butan-2-yl]-5-(trifluoromethyl)benzamide'>SKV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ENPP2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9598 Chimpansee troglodytes])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w35 OCA], [http://pdbe.org/6w35 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w35 RCSB], [http://www.ebi.ac.uk/pdbsum/6w35 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w35 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent and selective inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective and bioavailable small molecule. Co-crystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates. | ||
| + | |||
| + | A Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry.,Cuozzo JW, Clark MA, Keefe AD, Kohlmann A, Mulvihill MJ, Ni H, Renzetti L, Resnicow DI, Ruebsam F, Sigel EA, Thomson HA, Wang C, Xie Z, Zhang Y J Med Chem. 2020 Jun 25. doi: 10.1021/acs.jmedchem.0c00688. PMID:32584034<ref>PMID:32584034</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6w35" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures|Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Chimpansee troglodytes]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Cuozzo | + | [[Category: Cuozzo, J W]] |
| + | [[Category: Autotaxin]] | ||
| + | [[Category: Lipid binding protein]] | ||
Revision as of 05:57, 5 August 2020
A new Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry
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