학술논문
Discovery of a Potent and Selective CCR4 Antagonist That Inhibits TregTrafficking into the Tumor Microenvironment
Document Type
Article
Author
Jackson, Jeffrey J.; Ketcham, John M.; Younai, Ashkaan; Abraham, Betty; Biannic, Berenger; Beck, Hilary P.; Bui, Minna H. T.; Chian, David; Cutler, Gene; Diokno, Raymond; Hu, Dennis X.; Jacobson, Scott; Karbarz, Emily; Kassner, Paul D.; Marshall, Lisa; McKinnell, Jenny; Meleza, Cesar; Okal, Abood; Pookot, Deepa; Reilly, Maureen K.; Robles, Omar; Shunatona, Hunter P.; Talay, Oezcan; Walker, James R.; Wadsworth, Angela; Wustrow, David J.; Zibinsky, Mikhail
Source
Journal of Medicinal Chemistry; July 2019, Vol. 62 Issue: 13 p6190-6213, 24p
Subject
Language
ISSN
00222623; 15204804
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 Tregexpress CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, Tregaccumulation correlates with poor patient prognosis. Preclinical data suggests that preventing the recruitment of Tregand 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.