8jba

From Proteopedia

(Difference between revisions)

Current revision

Discovery and Crystallography Study of Novel Oxadiazole Analogs as Small Molecule PD-1/PD-L1 inhibitors

Structural highlights

8jba 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 2.6Å
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

Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as small-molecule PD-1/PD-L1 inhibitors. Among them, compound LP23 exhibited the most potent PD-L1 inhibitory activity with an IC(50) of 16.7 nM, 3.2-fold better than the lead BMS-202 (IC(50) = 53.6 nM). The X-ray crystal structure of LP23 in complex with PD-L1 was solved at a resolution of 2.6 A, which further confirmed the high binding affinity of LP23 to PD-L1. In the HepG2/Jurkat T cell co-culture model, LP23 effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, LP23 showed excellent in vivo antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, LP23 represents the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.

Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents.,Liu J, Cheng Y, Yuan L, Liu T, Ruan Y, Ren Y, Li L, Jiang S, Xiao Y, Chen J J Med Chem. 2023 Sep 28;66(18):13172-13188. doi: 10.1021/acs.jmedchem.3c01141. , Epub 2023 Sep 6. PMID:37674362^[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
↑ Liu J, Cheng Y, Yuan L, Liu T, Ruan Y, Ren Y, Li L, Jiang S, Xiao Y, Chen J. Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents. J Med Chem. 2023 Sep 28;66(18):13172-13188. PMID:37674362 doi:10.1021/acs.jmedchem.3c01141

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/8jba"

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

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8jba is ON HOLD
+==Discovery and Crystallography Study of Novel Oxadiazole Analogs as Small Molecule PD-1/PD-L1 inhibitors==
+<StructureSection load='8jba' size='340' side='right'caption='[[8jba]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8jba]] 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=8JBA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JBA 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]] 2.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AU9:(2~{S})-2-[[3-[[5-[(2-methyl-3-phenyl-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]sulfanylmethyl]phenyl]methylamino]-3-oxidanyl-propanoic+acid'>AU9</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=8jba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jba OCA], [https://pdbe.org/8jba PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jba RCSB], [https://www.ebi.ac.uk/pdbsum/8jba PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jba 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 ==
+Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as small-molecule PD-1/PD-L1 inhibitors. Among them, compound LP23 exhibited the most potent PD-L1 inhibitory activity with an IC(50) of 16.7 nM, 3.2-fold better than the lead BMS-202 (IC(50) = 53.6 nM). The X-ray crystal structure of LP23 in complex with PD-L1 was solved at a resolution of 2.6 A, which further confirmed the high binding affinity of LP23 to PD-L1. In the HepG2/Jurkat T cell co-culture model, LP23 effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, LP23 showed excellent in vivo antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, LP23 represents the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.
-Authors:
+Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents.,Liu J, Cheng Y, Yuan L, Liu T, Ruan Y, Ren Y, Li L, Jiang S, Xiao Y, Chen J J Med Chem. 2023 Sep 28;66(18):13172-13188. doi: 10.1021/acs.jmedchem.3c01141. , Epub 2023 Sep 6. PMID:37674362<ref>PMID:37674362</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 8jba" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Cheng Y]]
+[[Category: Xiao YB]]

8jba

From Proteopedia

Current revision

Discovery and Crystallography Study of Novel Oxadiazole Analogs as Small Molecule PD-1/PD-L1 inhibitors

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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