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.