| Literature DB >> 31882297 |
Satyamaheshwar Peddibhotla1, Paul M Hershberger2, R Jason Kirby2, Eliot Sugarman2, Patrick R Maloney2, E Hampton Sessions2, Daniela Divlianska2, Camilo J Morfa2, David Terry2, Anthony B Pinkerton2, Layton H Smith2, Siobhan Malany3.
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.Entities:
Keywords: Azabicyclononane scaffold; B-arrestin signaling; CXCR6 receptor antagonist; Hepatocellular carcinoma; SK-HEP xenograft model
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Year: 2019 PMID： 31882297 PMCID： PMC8011643 DOI： 10.1016/j.bmcl.2019.126899
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823