RAPT Therapeutics, 561 Eccles Avenue, South San Francisco, California 94080, United States.
J Med Chem. 2020 Aug 13;63(15):8584-8607. doi: 10.1021/acs.jmedchem.0c00988. Epub 2020 Jul 28.
The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (T) as well as other circulating and tissue-resident T cells. T can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. T 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 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 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 and models, is described herein.
C-C 趋化因子受体 4（CCR4）广泛表达于调节性 T 细胞（T）以及其他循环和组织驻留的 T 细胞上。T 细胞可以通过 C-C 趋化因子 CCL17 和 CCL22 募集到肿瘤微环境（TME）中。T 细胞在 TME 中的聚集已被证明会抑制抗肿瘤免疫反应，被认为是肿瘤免疫逃逸的重要驱动因素。临床前和临床数据表明，减少 TME 中的 T 细胞群可以增强检查点抑制剂的抗肿瘤免疫反应。我们已经开发了一种新型哌啶基氮杂环丁烷基 CCR4 小分子拮抗剂，可抑制 T 细胞向 TME 的募集，并作为单一药物或与免疫检查点阻断剂联合发挥抗肿瘤作用。本文描述了这些强效、选择性和可口服生物利用的 CCR4 拮抗剂的发现及其在 和 模型中的活性。
