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

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.
Jeffrey J Jackson 1,  John M Ketcham 1,  Ashkaan Younai 1,  Betty Abraham 1,  Berenger Biannic 1,  Hilary P Beck 1,  Minna H T Bui 1,  David Chian 1,  Gene Cutler 1,  Raymond Diokno 1,  Dennis X Hu 1,  Scott Jacobson 1,  Emily Karbarz 1,  Paul D Kassner 1,  Lisa Marshall 1,  Jenny McKinnell 1,  Cesar Meleza 1,  Abood Okal 1,  Deepa Pookot 1,  Maureen K Reilly 1,  Omar Robles 1,  Hunter P Shunatona 1,  Oezcan Talay 1,  James R Walker 1,  Angela Wadsworth 1,  David J Wustrow 1,  Mikhail Zibinsky 1
Affiliations

Affiliation

  • 1 RAPT Therapeutics , 561 Eccles Avenue , South San Francisco , California 94080 , United States.
PMID: 31259550 DOI: 10.1021/acs.jmedchem.9b00506
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.

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