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==Discovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis that Promotes PD-L1 Internalization and Degradation==
==Discovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis that Promotes PD-L1 Internalization and Degradation==
<StructureSection load='7dy7' size='340' side='right'caption='[[7dy7]]' scene=''>
<StructureSection load='7dy7' size='340' side='right'caption='[[7dy7]], [[Resolution|resolution]] 2.42&Aring;' 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=7DY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DY7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[7dy7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DY7 FirstGlance]. <br>
</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=7dy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dy7 OCA], [https://pdbe.org/7dy7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dy7 RCSB], [https://www.ebi.ac.uk/pdbsum/7dy7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dy7 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=HOU:2-[[3-[[5-(2-methyl-3-phenyl-phenyl)-1,3,4-oxadiazol-2-yl]amino]phenyl]methylamino]ethanol'>HOU</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=7dy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dy7 OCA], [https://pdbe.org/7dy7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dy7 RCSB], [https://www.ebi.ac.uk/pdbsum/7dy7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dy7 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/PD1L1_HUMAN PD1L1_HUMAN]] Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production.<ref>PMID:10581077</ref> <ref>PMID:11015443</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Several monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway have been used successfully in anticancer immunotherapy. Inherent limitations of antibody-based therapies remain, however, and alternative small-molecule inhibitors that can block the PD-1/PD-L1 axis are urgent needed. Herein, we report the discovery of compound 17 as a bifunctional inhibitor of PD-1/PD-L1 interactions. 17 inhibits PD-1/PD-L1 interactions and promotes dimerization, internalization, and degradation of PD-L1. 17 promotes cell-surface PD-L1 internalized into the cytosol and induces the degradation of PD-L1 in tumor cells through a lysosome-dependent pathway. Furthermore, 17 suppresses tumor growth in vivo by activating antitumor immunity. These results demonstrate that 17 targets the PD-1/PD-L1 axis and induces PD-L1 degradation.
Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation.,Wang T, Cai S, Cheng Y, Zhang W, Wang M, Sun H, Guo B, Li Z, Xiao Y, Jiang S J Med Chem. 2022 Mar 10;65(5):3879-3893. doi: 10.1021/acs.jmedchem.1c01682. Epub , 2022 Feb 21. PMID:35188766<ref>PMID:35188766</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7dy7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Cheng Y]]
[[Category: Cheng, Y]]
[[Category: Jiang S]]
[[Category: Jiang, S]]
[[Category: Lu ML]]
[[Category: Lu, M L]]
[[Category: Wang TY]]
[[Category: Wang, T Y]]
[[Category: Xiao YB]]
[[Category: Xiao, Y B]]
[[Category: Complex]]
[[Category: Dimer]]
[[Category: Immune checkpoint]]
[[Category: Immunosuppressant]]
[[Category: Inhibitor]]
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