1. 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.
- Author
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Peddibhotla S, Hershberger PM, Jason Kirby R, Sugarman E, Maloney PR, Hampton Sessions E, Divlianska D, Morfa CJ, Terry D, Pinkerton AB, Smith LH, and Malany S
- Subjects
- 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 metabolism, Signal Transduction drug effects, Small Molecule Libraries metabolism, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, Structure-Activity Relationship, Transplantation, Heterologous, Receptors, CXCR6 antagonists & inhibitors, Small Molecule Libraries chemistry
- 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 (EC
50 = 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2020
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