Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment

J Med Chem. 2019 Jul 11;62(13):6190-6213. doi: 10.1021/acs.jmedchem.9b00506. Epub 2019 Jul 1.


Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, Treg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of Treg and increasing the population of activated effector T cells (Teff) in the TME can potentiate antitumor immune responses. We developed a novel series of potent, orally bioavailable small molecule antagonists of CCR4. From this series, several compounds exhibited high potency in distinct functional assays in addition to good in vitro and in vivo ADME properties. The design, synthesis, and SAR of this series and confirmation of its in vivo activity are reported.

MeSH terms

  • Animals
  • Cell Movement / drug effects*
  • Cyclohexanes / chemical synthesis
  • Cyclohexanes / pharmacokinetics
  • Cyclohexanes / pharmacology
  • Drug Discovery
  • Humans
  • Mice, Transgenic
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Pyrazines / chemical synthesis
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Rats
  • Receptors, CCR4 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • T-Lymphocytes, Regulatory / drug effects*
  • Tumor Microenvironment / drug effects*


  • CCR4 protein, human
  • Ccr4 protein, mouse
  • Cyclohexanes
  • Piperazines
  • Pyrazines
  • Pyrazoles
  • Receptors, CCR4