Preclinical assessment of dihydroquinolinone inhibitors directly targeting oncogene TFCP2 as cancer therapeutics
Embargo Date
2024-06-16
OA Version
Citation
Abstract
The transcription factor TFCP2 is a pro-oncogenic factor in hepatocellular carcinoma, colorectal cancer, pancreatic cancer, breast cancer, glioma, rhabdomyosarcoma, squamous cell sarcoma, cervical cancer and ovarian cancer. TFCP2 promotes cell proliferation, invasion, angiogenesis, stemness and epithelial mesenchymal transition to stimulate cancer pathogenesis. The dynamic role of TFCP2 in cancer establishes it as a novel target for cancer therapeutics. A library of dihydroquinolinones, termed Factor Quinolinone Inhibitors (FQIs), inhibits TFCP2-DNA binding and specific TFCP2-protein interactions in in vitro and in cellular assays. The initial lead, racemic FQI-1, causes dramatic mitotic defects in HCC cell lines and reduces tumor growth in multiple cancer models, with no evidence of associated toxicity. FQI-1 had limited bioavailability. Further compound optimization focused on improving solubility, potency and pharmacokinetic profile with a focus on generating achiral compounds to avoid isolating enantiomers from the racemate. The anti-cancer effects of the new FQI compounds were evaluated in cancer cell lines with TFCP2 dysregulation. From the new structure activity relationship (SAR), a series of achiral compounds were generated, and their potency, absorption and metabolism (ADME) profile were evaluated in biological assays. The achiral compound, FQI2-34 emerged as a lead with moderate solubility, nanomolar potency and excellent ADME profile in in vitro assays. The lead FQI2-34 inhibits the TFCP2 transcriptional activities in dual luciferase reporter assay and binds to TFCP2 in cellular thermal shift assays. The application of FQIs were further evaluated in hepatocellular, pancreatic and colorectal cancer cell lines. The FQIs show encouraging preclinical efficacy in vitro assays and in mouse xenograft models of hepatocellular carcinoma (HCC) and colorectal cancer. The dihydroquinolinones are promising small molecule chemotherapeutics for TFCP2-driven cancers such as HCC, colorectal cancer, and pancreatic cancer.