Abstract
Novel small molecule compounds based on various scaffolds including chalcone, flavonoid, and resorcinol dibenzyl ether were designed and tested for their inhibitory activity against the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) pathway. Among them, compound NP19 inhibited the human PD-1/PD-L1 interaction with IC50 values of 12.5 nM in homogeneous time-resolved fluorescence (HTRF) binding assays. In addition, NP19 dose-dependently elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, NP19 displayed significant in vivo antitumor efficacy in two different mouse models of cancer (a melanoma B16-F10 tumor model and an H22 hepatoma tumor model). Moreover, H&E staining and flow cytometry data suggested that NP19 activated the immune microenvironment in the tumor, which may contribute to its antitumor effects. This work shows NP19 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the PD-1/PD-L1 pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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B7-H1 Antigen / antagonists & inhibitors*
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B7-H1 Antigen / metabolism
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / metabolism
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Cell Line, Tumor
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Drug Discovery
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Humans
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Liver Neoplasms / drug therapy
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Liver Neoplasms / metabolism
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Male
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / metabolism
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Mice
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Mice, Inbred BALB C
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Molecular Docking Simulation
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Phenyl Ethers / chemistry
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Phenyl Ethers / pharmacology*
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Phenyl Ethers / therapeutic use
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Programmed Cell Death 1 Receptor / metabolism
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Protein Interaction Maps / drug effects
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Rats, Sprague-Dawley
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Resorcinols / chemistry
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Resorcinols / pharmacology*
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Resorcinols / therapeutic use
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Signal Transduction / drug effects
Substances
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Antineoplastic Agents
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B7-H1 Antigen
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Phenyl Ethers
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Programmed Cell Death 1 Receptor
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Resorcinols
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dibenzyl ether