2. Academic Validation
  3. 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

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.
Satyamaheshwar Peddibhotla 1,  Paul M Hershberger 2,  R Jason Kirby 2,  Eliot Sugarman 2,  Patrick R Maloney 2,  E Hampton Sessions 2,  Daniela Divlianska 2,  Camilo J Morfa 2,  David Terry 2,  Anthony B Pinkerton 2,  Layton H Smith 2,  Siobhan Malany 3
Affiliations

Affiliations

  • 1 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 2 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 3 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA. Electronic address: [email protected].
PMID: 31882297 DOI: 10.1016/j.bmcl.2019.126899
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.

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