Single Agent and Synergistic Activity of the "First-in-Class" Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma

Mol Cancer Ther. 2016 Nov;15(11):2553-2562. doi: 10.1158/1535-7163.MCT-15-0976. Epub 2016 Aug 5.

Abstract

Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK, and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI3K/BRD4 inhibitors, which can be used either alone or in combination with sorafenib to treat patients with advanced HCC. Herein, we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with sorafenib inhibited proliferation, cell cycle, apoptosis, and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep3B, HepG2, SK-Hep1, and Huh7 HCC cell lines. We demonstrate that the active moiety of the SF1126 prodrug LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaced BRD4 coactivator protein from the transcriptional start site of MYC in Huh7 and SK-Hep1 HCC cell lines. Moreover, SF1126 blocked expression levels of c-Myc in HCC cells. Treatment of SF1126 either alone or in combination with sorafenib showed significant antitumor activity in vivo Our results establish that SF1126 is a dual PI3K/BRD4 inhibitor. This agent has completed a phase I clinical trial in humans with good safety profile. Our data support the potential future consideration of a phase II clinical trial of SF1126, a clinically relevant dual "first-in-class" PI3K/BRD4 inhibitor in advanced HCC, and a potential combination with sorafenib. Mol Cancer Ther; 15(11); 2553-62. ©2016 AACR.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle / drug effects
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chromones / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Genes, myc
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Mice
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Oligopeptides / pharmacology*
  • Phenylurea Compounds / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Sorafenib
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism
  • Transcription Initiation Site
  • Xenograft Model Antitumor Assays
  • raf Kinases / metabolism
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Chromones
  • Nuclear Proteins
  • Oligopeptides
  • Phenylurea Compounds
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • SF 1126
  • Transcription Factors
  • Niacinamide
  • Sorafenib
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • raf Kinases
  • ras Proteins