View source for 6pu7


==Human IDO1 in complex with compound 17 (N-{2-[(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N'-hydroxycarbamimidoyl}-1,2,5-oxadiazol-3-yl)sulfanyl]ethyl}acetamide)==
<StructureSection load='6pu7' size='340' side='right'caption='[[6pu7]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6pu7]] 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=6PU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PU7 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]] 2.43&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=OY4:N-{2-[(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-hydroxycarbamimidoyl}-1,2,5-oxadiazol-3-yl)sulfanyl]ethyl}acetamide'>OY4</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=6pu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pu7 OCA], [https://pdbe.org/6pu7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pu7 RCSB], [https://www.ebi.ac.uk/pdbsum/6pu7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pu7 ProSAT]</span></td></tr>
</table>
== 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> 
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== Publication Abstract from PubMed ==
Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.,Zhang H, Liu K, Pu Q, Achab A, Ardolino MJ, Cheng M, Deng Y, Doty AC, Ferguson H, Fradera X, Knemeyer I, Kurukulasuriya R, Lam YH, Lesburg CA, Martinot TA, McGowan MA, Miller JR, Otte K, Biju PJ, Sciammetta N, Solban N, Yu W, Zhou H, Wang X, Bennett DJ, Han Y ACS Med Chem Lett. 2019 Sep 18;10(11):1530-1536. doi:, 10.1021/acsmedchemlett.9b00344. eCollection 2019 Nov 14. PMID:31749906<ref>PMID:31749906</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 6pu7" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dioxygenase 3D structures|Dioxygenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lesburg CA]]