Novel Indazole‐based MKK7–TIPRL Interaction Inhibitors as TRAIL Sensitizers

Abstract

This work describes the process by which a metabolically unstable TRT‐0002 compound exhibiting Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐sensitizing activity for Huh7 cells at a high working concentration (40 μM) is converted to more potent and metabolically improved analogues by modifying the 5‐amino group and the 1‐aryl moiety in the 1H‐indazole skeleton. The efforts enabled us to identify 5‐sulfonamido derivatives, TRT‐0029 and TRT‐0173 compounds, working at lower concentrations (10 and 20 μM, respectively) and with improved metabolic stabilities. As reported previously by us, co‐treating cultured Huh7 cells with either TRT‐0029 or TRT‐0173 and TRAIL resulted in TRAIL‐induced apoptosis due to the inhibition of the MKK7–TOR signaling pathway regulator‐like (TIPRL) interaction and subsequent phosphorylation of MKK7 and JNK. In addition, the injection of TRT‐0029 or TRT‐0173 compound suppressed tumor growth in combination with TRAIL in an in vivo hepatocellular carcinoma (HCC) mouse xenograft model. TRT‐0029 and TRT‐0173 compounds and the relevant structure–activity relationship can provide an insight into further study on optimization of potency and metabolic stability.