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

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Jackson JJ,Ketcham JM,Younai A,Abraham B,Biannic B,Beck HP,Bui MHT,Chian D,Cutler G,Diokno R,Hu DX,Jacobson S,Karbarz E,Kassner PD,Marshall L,McKinnell J,Meleza C,Okal A,Pookot D,Reilly MK,Robles O,Shunatona HP

doi

10.1021/acs.jmedchem.9b00506

subject

Has Abstract

pub_date

2019-07-11 00:00:00

pages

6190-6213

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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