5whr: Difference between revisions
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<StructureSection load='5whr' size='340' side='right'caption='[[5whr]], [[Resolution|resolution]] 2.28Å' scene=''> | <StructureSection load='5whr' size='340' side='right'caption='[[5whr]], [[Resolution|resolution]] 2.28Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5whr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WHR OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5whr]] is a 2 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=5WHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WHR FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AOJ:( | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.28Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AOJ:(3~{R})-3-(5-fluoranyl-1~{H}-indol-3-yl)pyrrolidine-2,5-dione'>AOJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5whr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5whr OCA], [https://pdbe.org/5whr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5whr RCSB], [https://www.ebi.ac.uk/pdbsum/5whr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5whr ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/I23O1_HUMAN I23O1_HUMAN] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.<ref>PMID:17671174</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Feng | [[Category: Feng JL]] | ||
[[Category: Greasley | [[Category: Greasley SE]] | ||
[[Category: Kaiser | [[Category: Kaiser SE]] | ||
[[Category: Stewart | [[Category: Stewart A]] | ||
Latest revision as of 11:52, 9 October 2024
Discovery of a novel and selective IDO-1 inhibitor PF-06840003 and its characterization as a potential clinical candidate.Discovery of a novel and selective IDO-1 inhibitor PF-06840003 and its characterization as a potential clinical candidate.
Structural highlights
FunctionI23O1_HUMAN Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1] Publication Abstract from PubMedTumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h. Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate.,Crosignani S, Bingham P, Bottemanne P, Cannelle H, Cauwenberghs S, Cordonnier M, Dalvie D, Deroose F, Feng JL, Gomes B, Greasley S, Kaiser SE, Kraus M, Negrerie M, Maegley K, Miller N, Murray BW, Schneider M, Soloweij J, Stewart AE, Tumang J, Torti VR, Van Den Eynde B, Wythes M J Med Chem. 2017 Dec 14;60(23):9617-9629. doi: 10.1021/acs.jmedchem.7b00974. Epub, 2017 Nov 21. PMID:29111717[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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