Discovery of Novel Resorcinol Dibenzyl Ethers Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction as Potential Anticancer Agents

J Med Chem. 2020 Aug 13;63(15):8338-8358. doi: 10.1021/acs.jmedchem.0c00574. Epub 2020 Jul 30.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / metabolism
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Drug Discovery
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism
  • Male
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacology*
  • Phenyl Ethers / therapeutic use
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Protein Interaction Maps / drug effects
  • Rats, Sprague-Dawley
  • Resorcinols / chemistry
  • Resorcinols / pharmacology*
  • Resorcinols / therapeutic use
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • B7-H1 Antigen
  • Phenyl Ethers
  • Programmed Cell Death 1 Receptor
  • Resorcinols
  • dibenzyl ether