Discovery of Novel Tubulin CBSI (R)-9k from Indanone Scaffold for the Treatment of Colorectal Cancer

In view of the serious adverse reactions and clinical toxicity of first line therapy 5-Fluorouracil and lack of small molecule therapeutics in colorectal cancer chemotherapy{,} a series of natural scaffold-based 3-arylindanone derivatives (9a-q) were designed{,} synthesized and evaluated as tubulin polymerization inhibitors targeting colchicine site. The most potent colchicine binding site inhibitor (CBSI){,} (R)-9k{,} possessed 14-38 times dominant anti-proliferative activity against three colon cancer cell lines than 5-Fluorouracil. Particularly{,} (R)-9k showed higher selectivity against human normal cells compared with 5-Fluorouracil and colchicine{,} and displayed negligible cardiotoxicity through hERG assessment. Furthermore{,} the binding of (R)-9k to the colchicine site was strongly supported by EBI competition assay and (R)-9k inhibited more tubulin polymerization than colchicine. Besides{,} the mechanism of action and binding modes of (R)-9k were verified by molecular dynamics simulations and docking. Therefore{,} (R)-9k could be regarded as a promising CBSI for colorectal cancer therapy.