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8k5n

From Proteopedia

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Discovery of Novel PD-L1 Inhibitors That Induce Dimerization and Degradation of PD-L1 Based on Fragment Coupling Strategy

Structural highlights

8k5n is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

Publication Abstract from PubMed

Tumor cells can evade immune surveillance through overexpressing programmed cell death-ligand 1 (PD-L1) to interact with programmed cell death-1 (PD-1). Besides, tumor-intrinsic PD-L1 is involved in tumor progression without interaction with PD-1, which provides more challenges for the discovery of PD-L1 inhibitors. Herein, we report the discovery of novel PD-L1 inhibitors using the fragment coupling strategy. Among them, B9 was found to inhibit the PD-1/PD-L1 interaction with the best IC(50) value of 1.8 +/- 0.7 nM. Beyond the blockade of the PD-1/PD-L1 axis, B9 promotes the dimerization, internalization, and degradation of PD-L1. Furthermore, B9 displayed high in vivo antitumor efficacy in the CT26 mouse model and activated the immune microenvironment and induced PD-L1 degradation of PD-L1 in the tumor. These results show that B9 is a promising lead PD-L1 inhibitor through the blockade of PD-1/PD-L1 interaction and functional inhibition of the PD-L1 signal pathway.

Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.,Wang K, Zhang X, Cheng Y, Qi Z, Ye K, Zhang K, Jiang S, Liu Y, Xiao Y, Wang T J Med Chem. 2023 Dec 28;66(24):16807-16827. doi: 10.1021/acs.jmedchem.3c01534. , Epub 2023 Dec 18. PMID:38109261^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999 Dec;5(12):1365-9. PMID:10581077 doi:10.1038/70932
↑ Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000 Oct 2;192(7):1027-34. PMID:11015443
↑ Wang K, Zhang X, Cheng Y, Qi Z, Ye K, Zhang K, Jiang S, Liu Y, Xiao Y, Wang T. Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy. J Med Chem. 2023 Dec 28;66(24):16807-16827. PMID:38109261 doi:10.1021/acs.jmedchem.3c01534

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8k5n"

Categories: Homo sapiens | Large Structures | Cheng Y | Xiao YB

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8k5n is ON HOLD  until Paper Publication
+==Discovery of Novel PD-L1 Inhibitors That Induce Dimerization and Degradation of PD-L1 Based on Fragment Coupling Strategy==
+<StructureSection load='8k5n' size='340' side='right'caption='[[8k5n]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8k5n]] 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=8K5N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8K5N 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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I7M:3-[(1~{S})-1-[6-methoxy-3-methyl-5-[[[(2~{S})-5-oxidanylidenepyrrolidin-2-yl]methylamino]methyl]pyridin-2-yl]oxy-2,3-dihydro-1~{H}-inden-4-yl]-2-methyl-~{N}-[5-[[[(2~{S})-5-oxidanylidenepyrrolidin-2-yl]methylamino]methyl]pyridin-2-yl]benzamide'>I7M</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=8k5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8k5n OCA], [https://pdbe.org/8k5n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8k5n RCSB], [https://www.ebi.ac.uk/pdbsum/8k5n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8k5n ProSAT]</span></td></tr>
+</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 ==
+Tumor cells can evade immune surveillance through overexpressing programmed cell death-ligand 1 (PD-L1) to interact with programmed cell death-1 (PD-1). Besides, tumor-intrinsic PD-L1 is involved in tumor progression without interaction with PD-1, which provides more challenges for the discovery of PD-L1 inhibitors. Herein, we report the discovery of novel PD-L1 inhibitors using the fragment coupling strategy. Among them, B9 was found to inhibit the PD-1/PD-L1 interaction with the best IC(50) value of 1.8 +/- 0.7 nM. Beyond the blockade of the PD-1/PD-L1 axis, B9 promotes the dimerization, internalization, and degradation of PD-L1. Furthermore, B9 displayed high in vivo antitumor efficacy in the CT26 mouse model and activated the immune microenvironment and induced PD-L1 degradation of PD-L1 in the tumor. These results show that B9 is a promising lead PD-L1 inhibitor through the blockade of PD-1/PD-L1 interaction and functional inhibition of the PD-L1 signal pathway.
-Authors:
+Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.,Wang K, Zhang X, Cheng Y, Qi Z, Ye K, Zhang K, Jiang S, Liu Y, Xiao Y, Wang T J Med Chem. 2023 Dec 28;66(24):16807-16827. doi: 10.1021/acs.jmedchem.3c01534. , Epub 2023 Dec 18. PMID:38109261<ref>PMID:38109261</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8k5n" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Cheng Y]]
+[[Category: Xiao YB]]

8k5n

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Current revision

Discovery of Novel PD-L1 Inhibitors That Induce Dimerization and Degradation of PD-L1 Based on Fragment Coupling Strategy

Structural highlights

Function

Publication Abstract from PubMed

References

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