Inhibition of hERG by ESEE suppresses the progression of colorectal cancer

•ESEE, as a derivative of Emodin, retains the original pharmacological effects of emodin while improving its bioavailability.•ESEE robustly inhibited tumor growth.•ESEE exert anticancer activity through direct binding with hERG.•ESEE modulates the hERG/FAK/PI3K/AKT-mediated cell apoptosis pathway, thereby suppressing the progression of colorectal cancer. Colorectal cancer (CRC) is one of the most common malignant cancers. Emodin is a lipophilic anthraquinone commonly found in medicinal herbs and known for its antitumor properties. However, its clinical utility has been hampered by low druggability. We designed and synthesized a new compound named Emodin succinimidyl ethyl ester (ESEE), which improves the bioavailability and preserves the original pharmacological effects of Emodin. In vitro, we have confirmed that ESEE induces apoptosis in colon cancer cells, suppresses cell proliferation, migration, and invasion, and inhibits the growth of subcutaneous transplantation tumors associated with colon cancer. And, in vivo, ESEE robustly inhibited tumor growth. Human Ether-a-go-go Related Gene (hERG) is aberrantly expressed in various cancer cells, where they play an important role in cancer progression. Focal adhesion kinase (FAK) is a tyrosine kinase overexpressed in cancer cells and plays an important role in the progression of tumors to a malignant phenotype. Mechanistically, the anti-CRC properties of ESEE are exerted through direct binding with hERG, which impedes the FAK/PI3K/AKT signaling axis-dependent apoptotic cascade.