Prodrugs of the cancer cell selective anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally efficacious in a mouse model of resistant colon cancer.

•A131 possesses a unique cancer cell selective dual mechanism of action.•Prodrugs based on modification of the indole nitrogen of 1 undergo degradation to the parent drug in plasma.•Preferred prodrugs fully elicited the pharmacological effects of 1 in cells.•Preferred prodrugs and had high aqueous solubility suitable for oral administration.•In paclitaxel-resistant colon cancer xenograft model, 10 had 76% tumor growth inhibition when given orally at 80 mg/kg BID.