Development of novel Hepatocellular Carcinoma drugs, JNK-IN-5A derivatives simultaneously induce Apoptosis and Necrosis

In our previous study, we repurposed JNK-IN-5A to targeting PKLR gene which most co-related to hepatocellular carcinoma (HCC). Here, We showed anti HCC effect of JNK-IN-5A and its six derivative compounds SET135, SET156, SET158, SET159, SET171, and SET172 in HepG2 human HCC cell line. Compare to multi-target kinase inhibitor sorafenib and regorafenib, JNK-IN-5A and its 6 derivatives showed p53 induced cell cycle arrest, autophagy, apoptosis and reduced invasiveness. We found two derivatives which also has its own necrotic cell death pathway. SET135 showed p62/SQSTM1 induced autophgic necrotic cell death, and SET171 increased cellular ROS and lipid peroxidation induced necrotic cell death. Bioinformatics analysis also confirmed new derivatives has distinctive different cellular effect with stronger cell cycle arrest and apoptosis compare to sorafenib and regorfenib. Our new derivatives of JNK-IN-5A which has apoptotic and necrotic cell death inducer can be suggested as a new HCC drug candidate.