Discovery of Novel Pyrrolo[2,3‑<i>b</i>]pyridine-Based CSF-1R Inhibitors with Demonstrated Efficacy against Patient-Derived Colorectal Cancer Organoids

Repolarizing M2-like tumor associated macrophages (TAMs) into M1 phenotype by blocking CSF-1/CSF-1R signaling pathway represents a promising strategy to remodel the tumor immune microenvironment. Therefore, the discovery of novel potent CSF-1R inhibitors is of great significance for colorectal cancer immunotherapy. In this work, a series of novel CSF-1R inhibitors were designed and synthesized through rational molecular hybridization strategy and step by step structural optimization based on PLX3397 and BLZ945. Among these derivatives, compound III-1 was strongly bound to CSF-1R and showed potent CSF-1R inhibitory activity. It also effectively inhibited the activation of intracellular CSF-1R pathway and its downstream signaling events. Mechanically, III-1 efficiently repolarized M2-like TAMs into M1-phenotype, and inhibited the proliferation and promoted apoptosis of tumor cells through immunoregulation. More importantly, III-1 showed demonstrated efficacy against patient-derived colorectal cancer organoids and exhibited stronger anticolorectal cancer efficacy in vivo compared to PLX3397, highlighting its potential in the immunotherapy of colorectal cancer.