Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
J Med Chem. 2021 Dec 9;64(23):17184-17208. doi: 10.1021/acs.jmedchem.1c01184. Epub 2021 Nov 4.
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 ()-1-(3-((1-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 was found to possess excellent CSF-1R inhibitory activity (IC = 2.1 nM) and potent antiproliferative activity against colorectal cancer cells. Compound 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 , as a single agent, showed significantly superior anticolorectal cancer efficacy over PLX3397, highlighting a promising candidate for the immunotherapy of colorectal cancer.
通过阻断 CSF-1/CSF-1R 信号转导来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途的策略。在此，设计、合成并评价了一系列 ()-1-(3-((1-吡咯-2-基)亚甲基)-2-氧代吲哚啉-6-基)-3-(异噁唑-3-基)脲衍生物，作为新型、口服高效 CSF-1R 抑制剂用于结直肠癌免疫治疗。在这些衍生物中，发现化合物 对 CSF-1R 具有优异的抑制活性（IC = 2.1 nM），并对结直肠癌细胞具有很强的抗增殖活性。化合物 通过抑制巨噬细胞的迁移、将 M2 样巨噬细胞重编程为 M1 表型以及增强抗肿瘤免疫来抑制结直肠癌的进展。更重要的是，化合物 作为单一药物，在抗结直肠癌方面的疗效明显优于 PLX3397，突显了其作为结直肠癌免疫治疗的有前途的候选药物。
