Novel small molecule inhibitors of the transcription factor ETS-1 and their antitumor activity against hepatocellular carcinoma

by Selleckchem | Nov 08 2023

The transcription factor ETS-1 (E26 transformation specific sequence 1) is the key regulator for malignant tumor cell proliferation and invasion by mediating the transcription of the invasion/migration related factors, e.g. MMPs (matrix metalloproteinases). This work aims to identify the novel small molecule inhibitors of ETS-1 using a small molecule compound library and to study the inhibitors' antitumor activity against hepatocellular carcinoma (HCC). The luciferase reporter is used to examine the inhibition and activation of ETS-1's transcription factor activity in HCC cells, including a highly invasive HCC cell line, MHCC97-H, and five lines of patient-derived cells. The inhibition of the proliferation of HCC cells is examined using the MTT assay, while the invasion of HCC cells is examined using the transwell assay. The anti-tumor activity of the selected compound on HCC cells is also examined in a subcutaneous tumor model or intrahepatic tumor model in nude mice. The results show that for the first time, four compounds, EI1~EI-4, can inhibit the transcription factor activation of ETS-1 and the proliferation or invasion of HCC cells. Among the four compounds, EI-4 has the best activation. The results from this paper contribute to expanding our understanding of ETS-1 and provide alternative, the safer and more effective, HCC molecular therapy strategies.

Comments:

This research work focuses on identifying small molecule inhibitors of the transcription factor ETS-1, which plays a crucial role in promoting malignant tumor cell proliferation and invasion by regulating the transcription of invasion/migration-related factors like MMPs. The study aims to find novel compounds that can inhibit ETS-1 activity and investigate their potential as antitumor agents against hepatocellular carcinoma (HCC).

To achieve this, the researchers use a small molecule compound library to screen for potential ETS-1 inhibitors. They employ a luciferase reporter assay to assess the inhibition and activation of ETS-1's transcription factor activity in HCC cells, including a highly invasive HCC cell line called MHCC97-H, as well as five patient-derived HCC cell lines. The researchers also examine the effect of the compounds on the proliferation and invasion of HCC cells using the MTT assay and the transwell assay, respectively.

Moreover, the study evaluates the anti-tumor activity of the selected compound in animal models of HCC. They employ subcutaneous tumor models or intrahepatic tumor models in nude mice to assess the compound's efficacy in inhibiting HCC growth and invasion.

The findings indicate that four compounds, EI1~EI-4, exhibit the ability to inhibit ETS-1's transcription factor activation, as well as hinder the proliferation and invasion of HCC cells. Among these compounds, EI-4 demonstrates the most potent inhibitory effect.

Overall, the results contribute significantly to our understanding of the role of ETS-1 in HCC and open up new possibilities for developing safer and more effective molecular therapies for this type of cancer. These findings are promising and suggest that further research on the identified compounds could lead to potential treatments for HCC.