5whr: Difference between revisions

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'''Unreleased structure'''


The entry 5whr is ON HOLD until Paper Publication
==Discovery of a novel and selective IDO-1 inhibitor PF-06840003 and its characterization as a potential clinical candidate.==
<StructureSection load='5whr' size='340' side='right' caption='[[5whr]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
== 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WHR FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AOJ:(3R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione'>AOJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase Indoleamine 2,3-dioxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.13.11.52 1.13.11.52] </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=5whr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5whr OCA], [http://pdbe.org/5whr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5whr RCSB], [http://www.ebi.ac.uk/pdbsum/5whr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5whr ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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;">
== Publication Abstract from PubMed ==
Tumors 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.


Authors: Greasley, S.E., Kaiser, S.E., Feng, J.L., Stewart, A.
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<ref>PMID:29111717</ref>


Description: Discovery of a novel and selective IDO-1 inhibitor PF-06840003 and its characterization as a potential clinical candidate.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 5whr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Indoleamine 2,3-dioxygenase]]
[[Category: Feng, J L]]
[[Category: Greasley, S E]]
[[Category: Kaiser, S E]]
[[Category: Stewart, A]]
[[Category: Stewart, A]]
[[Category: Greasley, S.E]]
[[Category: Cancer immunotherapy]]
[[Category: Kaiser, S.E]]
[[Category: Oxidoreductase]]
[[Category: Feng, J.L]]
[[Category: Oxidoreductase-inhibitor complex]]
[[Category: Small molecule inhibitor]]

Revision as of 11:29, 27 December 2017

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

5whr is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Activity:Indoleamine 2,3-dioxygenase, with EC number 1.13.11.52
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[I23O1_HUMAN] Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1]

Publication Abstract from PubMed

Tumors 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.

References

  1. ↑ Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007 Aug 1;67(15):7082-7. PMID:17671174 doi:http://dx.doi.org/10.1158/0008-5472.CAN-07-1872
  2. ↑ 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. 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. J Med Chem. 2017 Dec 14;60(23):9617-9629. doi: 10.1021/acs.jmedchem.7b00974. Epub, 2017 Nov 21. PMID:29111717 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00974

5whr, resolution 2.28Å

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