Discovery of novel small molecule inhibitor targeting the tumor promoting effect of transcription factor PLAGL2

Pleiomorphic adenoma-like protein 2 (PLAGL2) is a key player in the development of hepatocellular carcinoma (HCC) and other malignant tumors. High levels of PLAGL2 expression are associated with poor prognosis in cancer. While the potential of PLAGL2 as a therapeutic target for HCC has been recognized, there is a lack of research on small-molecule inhibitors targeting PLAGL2. In this study, a series of small-molecule inhibitors of PLAGL2 transcriptional activity were developed through virtual screening and structure optimization. Among which, compounds C7 and C8 potently suppressed PLAGL2 transcriptional activity, leading to reduced proliferation, colony formation, migration, invasion, cell cycle arrest, and apoptosis in HCC cells. Compound C8 exhibited stronger binding affinity to PLALG2 than compound C7. Furthermore, C8 disrupted extracellular matrix organization and suppressed the PI3K-AKT pathway by reducing AKT phosphorylation. It effectively inhibited tumor growth in HCCLM3 xenograft tumor models while demonstrating a favorable safety profile. Taken together, this study introduces a promising 3-(Phenylsulfonamido) benzamide derivative as a novel approach to targeting PLAGL2 transcriptional activity, laying a foundation for future investigations in anti-tumor therapy.