Assessing the selectivity and efficacy of dihydroquinolinone inhibitors directly targeting the oncogene LSF

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second leading cause of cancer mortality. Despite the prevalence of HCC, there is only one FDA approved drug for the advanced disease, which extends lifespan by only 2-3 months and is associated with multiple side effects. Late SV40 Factor (LSF) has been shown to function as an oncogenic transcription factor in HCC, making it a promising protein target for HCC therapy. A library of dihydroquinolinones, termed FQIs, have been shown to inhibit LSF-DNA binding in in vitro and cellular assays. The lead compound FQI-1 causes dramatic mitotic defects in HCC cell lines, but has no or only limited growth effects on immortalized human hepatocytes or primary mouse hepatocytes. Additionally, FQI-1 has proven efficacious in in vivo HCC mouse models, with no evidence of associated toxicity. The dihydroquinolinones are promising compounds for a molecularly targeted therapy against HCC. Herein, the library of compounds was expanded and tested for potency in an aggressive HCC cell line, as well as for transactivation activity against the LSF and closely related family of transcription factors. Direct target engagement is shown for the first time with cellular thermal stability assays in HCC cell lysates. The lead compound is further shown to have a promising pharmacokinetic and tolerability profile in rats, supporting the development as a drug candidate. As a potential driver of mitosis, LSF may have a broader role in cancers beyond HCC. High-throughput screening identified hematopoietic cancer lineages as particularly sensitive to the dihydroquinolinones. As a proof-of-concept, the hematopoietic cell line U937 is shown to express high levels of LSF protein, and undergoes extensive apoptosis when treated with dihydroquinolinones or siRNA against the LSF subfamily.2019-11-03T00:00:00