Fluoroindole chalcone analogues targeting the colchicine binding site of tubulin for colorectal oncotherapy

Colorectal Cancer (CRC) is a common malignancy of the gastrointestinal tract with high morbidity and mortality. Our previous studies have demonstrated that indole-chalcone-based compounds targeting tubulin displayed potential cytotoxicity to CRC cells. Herein, three new series of derivatives were systematically designed and synthesized to explore their structure-activity relationship (SAR) against CRC based on prior research. Among them, a representative fluorine-containing analog (FC116) exerted superior efficacy on HCT116 (IC₅₀ = 4.52 nM) and CT26 (IC₅₀ = 18.69 nM) cell lines, and HCT116-xenograft mice with tumor growth inhibition rate of 65.96% (3 mg/kg). Of note, FC116 could also suppress the growth of organoid models (IC₅₀ = 1.8-2.5 nM) and showed adenoma number inhibition rate of 76.25% at the dose of 3 mg/kg in APC^min/+ mice. In terms of mechanism, FC116 could induce endoplasmic reticulum (ER) stress to produce excess Reactive Oxygen Species (ROS), leading to mitochondrial damage to promote the Apoptosis of CRC cells by targeting microtubules. Our results support that indole-chalcone compounds are promising tubulin inhibitors and highlight the potential of FC116 to combat CRC.

Chalcone; Colorectal cancer; ER stress; Fluoroindole; Microtubules.