Discovery of ( Z)-1-(3-((1 H-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.