Preclinical Lead Optimization of Small Molecule Inhibitors of TFCP2 (LSF) for the Treatment of Liver Cancer

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, necessitating novel therapeutic approaches.
• The oncogenic transcription factor LSF/TFCP2 plays a crucial role in HCC development.
• Existing treatments for HCC require new, effective therapeutic strategies.

Purpose of the Study:

• To identify and optimize novel dihydroquinolinone inhibitors targeting LSF/TFCP2 for hepatocellular carcinoma treatment.
• To evaluate the structure-activity relationships (SAR) of Factor Quinolinone Inhibitors (FQIs).
• To discover potent and bioavailable FQI analogs with significant in vivo antitumor activity.

Main Methods:

• Screening of a dihydroquinolinone library to identify inhibitors of LSF/TFCP2.
• Structure-activity relationship (SAR) studies of chiral and achiral FQI analogs.
• In vitro enzymatic assays and in vivo tumor suppression studies in HCC models.
• Assessment of ADME properties and TFCP2 binding affinities.

Main Results:

• Compound 1 was identified as a potent in vitro inhibitor of LSF/TFCP2 and an in vivo suppressor of HCC.
• Optimization of FQI analogs led to the discovery of achiral compound 12 (FQI2-34).
• Compound 12 (FQI2-34) demonstrated potent, selective antitumor activity with favorable ADME properties and nanomolar binding to TFCP2.

Conclusions:

• Factor Quinolinone Inhibitors (FQIs) are effective direct binders of TFCP2.
• Achiral FQI2-34 represents a promising therapeutic candidate for TFCP2-driven cancers, particularly HCC.
• FQIs offer a potential new class of chemotherapeutics for hepatocellular carcinoma.