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

Abstract

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.

The Underlying Roles of Exosome-Associated PIGR in Fatty Acid Metabolism and Immune Signaling in Colorectal Cancer

“…e combination of traditional treatment methods with immune checkpoint inhibitors could provide promising treatment strategies for cancer patients, including CRC [38]. Numerous studies have shown that immunotherapy can inhibit the growth of colorectal cancer cells and prolong the survival period of patients [39][40][41]. In this paper, the correlation between PIGR and immune-associated signatures was explored by comprehensive bioinformatic technologies.…”

Discovery of a Novel CSF-1R Inhibitor with Highly Improved Pharmacokinetic Profiles and Superior Efficacy in Colorectal Cancer Immunotherapy

“…In our previous work, through rational drug design on the basis of Sunitinib, a novel CSF-1R inhibitor B19 that can induce the transformation of M2-like TAMs to M1 and exhibits good anti-CRC effect was discovered . But in the subsequent evaluation of pharmacokinetic properties, we found that B19 had very low oral bioavailability ( F < 1%), which limited its further development.…”

Chiral Cyclopropenimine‐catalyzed Asymmetric Michael Addition of Bulky Glycine Imine to α,β‐Unsaturated Isoxazoles

“…In recent years, α,β-unsaturated isoxazoles [8][9][10][11][12] have been used as new type of Michael acceptor to install heterocyclic ring in organic molecules. The compounds containing isoxazole core exhibit unique bioactivities with anticancer, [13] antimicrobial [14] and anti-inflammatory effects. [15] The benzophenone-protected glycine derivatives (glycine imines) were used as readily available starting materials in many transformations including Michael addition, [16][17][18] alkylation [19][20][21] and [3 + 2] cycloaddition.…”