An Fc–Small Molecule Conjugate for Targeted Inhibition of the Adenosine 2A Receptor

Po Yuan Hsiao, Jay H. Kalin, Im Hong Sun, Mohammed N. Amin, Ying Chun Lo, Meng Jung Chiang, John Giddens, Polina Sysa-Shah, Kathleen Gabrielson, Lai Xi Wang, Jonathan D. Powell, Philip A. Cole

Research output: Contribution to journalArticlepeer-review


The adenosine A2A receptor (A2AR) is expressed in immune cells, as well as brain and heart tissue, and has been intensively studied as a therapeutic target for multiple disease indications. Inhibitors of the A2AR have the potential for stimulating immune response, which could be valuable for cancer immune surveillance and mounting a response against pathogens. One well-established potent and selective small molecule A2AR antagonist, ZM-241385 (ZM), has a short pharmacokinetic half-life and the potential for systemic toxicity due to A2AR effects in the brain and the heart. In this study, we designed an analogue of ZM and tethered it to the Fc domain of the immunoglobulin IgG3 by using expressed protein ligation. The resulting protein–small molecule conjugate, Fc–ZM, retained high affinity for two Fc receptors: FcγRI and the neonatal Fc receptor, FcRn. In addition, Fc–ZM was a potent A2AR antagonist, as measured by a cell-based cAMP assay. Cell-based assays also revealed that Fc–ZM could stimulate interferon γ production in splenocytes in a fashion that was dependent on the presence of A2AR. We found that Fc–ZM, compared with the small molecule ZM, was a superior A2AR antagonist in mice, consistent with the possibility that Fc attachment can improve pharmacokinetic and/or pharmacodynamic properties of the small molecule.

Original languageEnglish (US)
Pages (from-to)1951-1960
Number of pages10
Issue number20
StatePublished - Oct 17 2016


  • Fc domain
  • adenosine receptors
  • drug design
  • inhibitors
  • small molecules

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry


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