Discovery of (<i>Z</i>)‑1-(3-((1<i>H</i>‑Pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea Derivatives as Novel and Orally Highly Effective CSF-1R Inhibitors for Potential Colorectal Cancer Immunotherapy

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.通过阻断集落刺激因子1/集落刺激因子1受体（CSF-1/CSF-1R）信号通路，抑制肿瘤相关巨噬细胞（tumor-associated macrophages）的极化或存活，已成为肿瘤免疫治疗领域极具潜力的策略。本研究中，我们设计、合成并评价了一系列(Z)-1-(3-((1H-吡咯-2-基)亚甲基)-2-吲哚酮-6-基)-3-(异恶唑-3-基)脲类衍生物，作为用于结直肠癌免疫治疗的新型口服高效CSF-1R抑制剂。在该系列衍生物中，化合物21展现出优异的CSF-1R抑制活性（半数抑制浓度IC50=2.1 nM）以及对结直肠癌细胞的强效抗增殖活性。化合物21通过抑制巨噬细胞迁移、将M2样巨噬细胞重编程为M1型表型并增强抗肿瘤免疫，从而阻滞结直肠癌的进展。尤为重要的是，作为单一用药时，化合物21的体内抗结直肠癌疗效显著优于PLX3397，凸显其作为结直肠癌免疫治疗候选药物的良好应用前景。