Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors
| Autor: | Scott Jacobson, Dennis X. Hu, Cesar Meleza, Mikhail Zibinsky, Ashkaan Younai, Erin Riegler, Omar Robles, Jenny McKinnell, Emily Karbarz, Paul D. Kassner, Lisa A. Marshall, Maureen Kay Reilly, David Chian, Gene Cutler, David J. Wustrow, Dirk G. Brockstedt, Hunter P. Shunatona, Raymond Diokno, Angela Wadsworth, John M. Ketcham, Oezcan Talay, Jeffrey J. Jackson |
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| Rok vydání: | 2020 |
| Předmět: |
Chemokine
Receptors CCR4 Population CCR4 Antineoplastic Agents chemical and pharmacologic phenomena T-Lymphocytes Regulatory 01 natural sciences 03 medical and health sciences Chemokine receptor Dogs Immune system Piperidines Cell Line Tumor Neoplasms Drug Discovery Animals Humans CCL17 education 030304 developmental biology 0303 health sciences Tumor microenvironment education.field_of_study biology Chemistry Immune checkpoint 0104 chemical sciences Macaca fascicularis 010404 medicinal & biomolecular chemistry biology.protein Cancer research Azetidines Molecular Medicine sense organs |
| Zdroj: | Journal of Medicinal Chemistry. 63:8584-8607 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00988 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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