Novel Indazoie-based MKK7-TIPRL Interaction Inhibitors as TRAIL Sensitizers

摘要

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 (TTPRL) 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.