化学
结直肠癌
IC50型
癌症免疫疗法
体内
免疫疗法
癌症研究
癌症
体外
药理学
内科学
医学
生物化学
生物
生物技术
作者
Qi Lv,Xiang Pan,Dan Wang,Quanjin Rong,Ben Ma,Xiaolong Xie,Yinan Zhang,Junwei Wang,Lihong Hu
标识
DOI:10.1021/acs.jmedchem.1c01184
摘要
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.
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