Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors.

Autor:	Robles O; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Jackson JJ; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Marshall L; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Talay O; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Chian D; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Cutler G; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Diokno R; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Hu DX; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Jacobson S; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Karbarz E; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Kassner PD; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Ketcham JM; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., McKinnell J; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Meleza C; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Reilly MK; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Riegler E; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Shunatona HP; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Wadsworth A; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Younai A; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Brockstedt DG; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Wustrow DJ; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States., Zibinsky M; RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Aug 13; Vol. 63 (15), pp. 8584-8607. Date of Electronic Publication: 2020 Jul 28.
DOI:	10.1021/acs.jmedchem.0c00988
Abstrakt:	The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (T reg ) as well as other circulating and tissue-resident T cells. T reg can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. T reg 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 T reg 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 T reg 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:	MEDLINE
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