C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clinical setting. In the present study, we compared 10 existing human CCR2 antagonists in a calcium influx assay using human monocytic leukemia cells. Among them, MK0812 was found to be the most potent inhibitor of human CCR2. Furthermore, we generated a human CCR2B knock-in mouse model to test the efficacy of MK0812 against a lung metastasis model of breast cancer. Oral administration of MK0812 to humanized mice did indeed reduce the number of monocytic myeloid-derived suppressor cells and the rate of lung metastasis. These results suggest that MK0812 is the most promising candidate among the commercially available CCR2 inhibitors. We propose that combining these two screening methods may provide an excellent experimental method for identifying effective drugs that inhibit human CCR2.

中文翻译：

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使用人源化小鼠鉴定用于癌症治疗的有效 CCR2 抑制剂

CC趋化因子受体2型（CCR2）是CC基序趋化因子2（CCL2）的受体，与多种炎症性疾病和癌症转移相关。尽管已经开发出许多 CCR2 抑制剂，但哪种抑制剂在临床环境中最有效仍悬而未决。在本研究中，我们使用人单核细胞白血病细胞进行钙内流测定，比较了 10 种现有的人 CCR2 拮抗剂。其中，MK0812被发现是人类CCR2最有效的抑制剂。此外，我们构建了人类 CCR2B 敲入小鼠模型，以测试 MK0812 对乳腺癌肺转移模型的功效。人源化小鼠口服MK0812确实减少了单核细胞骨髓源性抑制细胞的数量和肺转移率。这些结果表明 MK0812 是市售 CCR2 抑制剂中最有前途的候选药物。我们认为，结合这两种筛选方法可能为鉴定抑制人 CCR2 的有效药物提供极好的实验方法。