Discovery of (Z)-1-(3-((1H-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
Discovery of (Z)-1-(3-((1H-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
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(Z)-1-(3-((1 H-吡咯-2-基)亚甲基)-2-氧代吲哚啉-6-基)-3-(异恶唑-3-基)脲衍生物的发现，为新型且口服高度的
DOI：
10.1021/acs.jmedchem.1c01184
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发表时间：
2021-12-09
影响因子：
7.3
通讯作者：
Hu, Lihong
中科院分区：
文献类型：
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作者：
Lv, Qi;Pan, Xiang;Hu, Lihong
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一种很有前景的癌症免疫治疗策略。本文设计、合成了一系列(Z)-1-（3-（（1h -吡咯-2-基）亚甲基）-2-氧吲哚林-6-基）-3-（异恶唑-3-基）尿素衍生物，并对其进行了评价，以作为结直肠癌免疫治疗的新型口服高效CSF-1R抑制剂。其中化合物21对结直肠癌细胞具有良好的CSF-1R抑制活性（IC50 = 2.1 nM）和较强的抗增殖活性。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，增强抗肿瘤免疫，抑制结直肠癌的进展。更重要的是，化合物21作为单药在体内的抗结直肠癌疗效明显优于PLX3397，是一种很有前景的大肠癌免疫治疗药物。
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.