基于片段的程序性死亡配体 1（PD-L1）筛选。
Fragment-based screening of programmed death ligand 1 (PD-L1).
机构信息
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232-0146, USA.
Vanderbilt Institute of Chemical Biology Synthesis Core, Vanderbilt University, Nashville, TN 37232-0146, USA.
出版信息
Bioorg Med Chem Lett. 2019 Mar 15;29(6):786-790. doi: 10.1016/j.bmcl.2019.01.028. Epub 2019 Jan 24.
Abstract
The PD-1 immune checkpoint pathway is a highly validated target for cancer immunotherapy. Despite the potential advantages of small molecule inhibitors over antibodies, the discovery of small molecule checkpoint inhibitors has lagged behind. To discover small molecule inhibitors of the PD-1 pathway, we have utilized a fragment-based approach. Small molecules were identified that bind to PD-L1 and crystal structures of these compounds bound to PD-L1 were obtained.
摘要
PD-1 免疫检查点途径是癌症免疫治疗的一个高度验证的靶点。尽管小分子抑制剂相对于抗体具有潜在的优势，但小分子检查点抑制剂的发现却落后了。为了发现 PD-1 途径的小分子抑制剂，我们利用了基于片段的方法。已经鉴定出了与 PD-L1 结合的小分子，并且获得了这些化合物与 PD-L1 结合的晶体结构。
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本文引用的文献
1
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J Immunother Cancer. 2018 Jan 23;6(1):8. doi: 10.1186/s40425-018-0316-z.
2
Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells.
Oncotarget. 2017 Aug 7;8(42):72167-72181. doi: 10.18632/oncotarget.20050. eCollection 2017 Sep 22.
3
Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint.
Angew Chem Int Ed Engl. 2017 Oct 23;56(44):13732-13735. doi: 10.1002/anie.201707707. Epub 2017 Sep 26.
4
Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2.
Structure. 2017 Aug 1;25(8):1163-1174. doi: 10.1016/j.str.2017.06.011.
5
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6
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Front Pharmacol. 2017 Feb 8;8:49. doi: 10.3389/fphar.2017.00049. eCollection 2017.
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