Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126899. doi: 10.1016/j.bmcl.2019.126899. Epub 2019 Dec 17.

Abstract

The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC50 = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.

Keywords: Azabicyclononane scaffold; B-arrestin signaling; CXCR6 receptor antagonist; Hepatocellular carcinoma; SK-HEP xenograft model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / metabolism
  • Azabicyclo Compounds / pharmacology
  • Azabicyclo Compounds / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptors, CXCR6 / antagonists & inhibitors*
  • Receptors, CXCR6 / metabolism
  • Signal Transduction / drug effects
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Azabicyclo Compounds
  • CXCR6 protein, human
  • Receptors, CXCR6
  • Small Molecule Libraries