Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment
| Autor: | Deepa Pookot, Scott Jacobson, John M. Ketcham, David Chian, Emily Karbarz, Dennis X. Hu, James Ross Walker, Gene Cutler, Ashkaan Younai, Mikhail Zibinsky, Raymond Diokno, David J. Wustrow, Betty Abraham, Angela Wadsworth, Maureen Kay Reilly, Cesar Meleza, Jenny McKinnell, Jeffrey J. Jackson, Abood Okal, Paul D. Kassner, Lisa A. Marshall, Oezcan Talay, Berenger Biannic, Bui Minna H T, Hilary Plake Beck, Hunter P. Shunatona, Omar Robles |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Tumor microenvironment education.field_of_study Chemistry Effector Population FOXP3 01 natural sciences 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Immune system In vivo Drug Discovery Cancer research Molecular Medicine CCL17 education CCL22 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 62:6190-6213 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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