Inhibiting the polarization or survival of tumor-associated macrophages through blocking CSF-1/CSF-1R signal transduction has become a promising strategy for cancer immunotherapy. Herein, a series of (Z)-1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea derivatives were designed, synthesized, and evaluated as novel and orally highly effective CSF-1R inhibitors for colorectal cancer immunotherapy. Among these derivatives, compound 21 was found to possess excellent CSF-1R inhibitory activity (IC₅₀ = 2.1 nM) and potent antiproliferative activity against colorectal cancer cells. Compound 21 inhibited the progression of colorectal cancer by suppressing the migration of macrophages, reprograming M2-like macrophages to the M1 phenotype, and enhancing the antitumor immunity. More importantly, compound 21, as a single agent, showed significantly superior in vivo anticolorectal cancer efficacy over PLX3397, highlighting a promising candidate for the immunotherapy of colorectal cancer.

中文翻译：

---

(Z)-1-(3-((1H-Pyrrol-2-yl)methylene)-2-oxindolin-6-yl)-3-(isoxazol-3-yl)脲衍生物的发现作为新型和口服高效用于潜在结直肠癌免疫治疗的 CSF-1R 抑制剂

通过阻断 CSF-1/CSF-1R 信号转导抑制肿瘤相关巨噬细胞的极化或存活已成为癌症免疫治疗的一种有前景的策略。在此，设计了一系列( Z )-1-(3-((1 H -pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)脲衍生物，合成并评估为用于结直肠癌免疫治疗的新型和口服高效 CSF-1R 抑制剂。在这些衍生物中，发现化合物21具有优异的 CSF-1R 抑制活性 (IC ₅₀ = 2.1 nM) 和对结肠直肠癌细胞的有效抗增殖活性。化合物21通过抑制巨噬细胞的迁移、将 M2 样巨噬细胞重编程为 M1 表型和增强抗肿瘤免疫力来抑制结直肠癌的进展。更重要的是，化合物21作为单一药物，在体内抗结直肠癌疗效显着优于PLX3397，突出了结直肠癌免疫治疗的有希望的候选者。