Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors
Omar Robles, Jeffrey J. Jackson, Lisa A. Marshall, Oezcan Talay, David Chian, Gene Cutler, Raymond Diokno, Dennis X. Hu, Scott Jacobson, Emily Karbarz, Paul D. Kassner, John M. Ketcham, Jenny McKinnell, Cesar Meleza, Maureen K. Reilly, Erin Riegler, Hunter P. Shunatona, Angela Wadsworth, Ashkaan Younai, Dirk G. Brockstedt, David J. Wustrow, Mikhail Zibinsky
Abstract
The C–C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (Treg) as well as other circulating and tissue-resident T cells. Treg can be recruited to the tumor microenvironment (TME) through the C–C chemokines CCL17 and CCL22. Treg accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion. Preclinical and clinical data suggest that reducing the Treg population in the TME can potentiate the antitumor immune response of checkpoint inhibitors. We have developed small-molecule antagonists of CCR4, featuring a novel piperidinyl-azetidine motif, that inhibit the recruitment of Treg into the TME and elicit antitumor responses as a single agent or in combination with an immune checkpoint blockade. The discovery of these potent, selective, and orally bioavailable CCR4 antagonists, and their activity in in vitro and in vivo models, is described herein.