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

Abstract

Recruitment of suppressive CD4⁺ FOXP3⁺ regulatory T cells (T_reg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human T_reg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, T_reg accumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of T_reg and increasing the population of activated effector T cells (T_eff) 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.