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

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality, underscoring the need for new therapeutic strategies. Screening a library of dihydroquinolinones, termed Factor Quinolinone Inhibitors (FQIs), identified compound 1 as a potent in vitro inhibitor of the oncogenic transcription factor LSF/TFCP2 and as an in vivo suppressor of HCC tumor growth without observable cytotoxicity. Unfortunately, 1 had limited bioavailability. In this report, we detail the identification and optimization of the structure–activity relationships (SAR) of chiral and achiral FQI analogs. The SAR study led to the discovery of achiral 12 (FQI2–34), a highly potent, selective compound with desirable absorption, distribution, metabolism, and excretion (ADME) properties and potent in vivo antitumor activity. We also demonstrated that FQIs directly bind to TFCP2 with affinities in the nanomolar ranges. Our results suggest that FQIs are promising chemotherapeutics for TFCP2-driven cancer, especially HCC.