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 <b>1</b> as a potent <i>in vitro</i> inhibitor of the oncogenic transcription factor LSF/TFCP2 and as an <i>in vivo</i> suppressor of HCC tumor growth without observable cytotoxicity. Unfortunately, <b>1</b> 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 <b>12 (FQI2-34)</b>, a highly potent, selective compound with desirable absorption, distribution, metabolism, and excretion (ADME) properties and potent <i>in vivo</i> 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.