title: Single Agent and Synergistic Activity of the "First-in-Class" Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma.
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.
authors: Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California.
authors: Alok R
authors: AR
authors: Singh
authors: Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California.
authors: Shweta
authors: S
authors: Joshi
authors: Division of Hematology-Oncology, Moores Cancer Center, University of California San Diego, La Jolla, California.
authors: Adam M
authors: AM
authors: Burgoyne
authors: Division of Surgical Oncology, Moores Cancer Center, University of California San Diego, La Jolla, California.
authors: Jason K
authors: JK
authors: Sicklick
authors: Division of Hematology-Oncology, Moores Cancer Center, University of California San Diego, La Jolla, California.
authors: Sadakatsu
authors: S
authors: Ikeda
authors: Division of Hepatology, Department of Medicine, University of California San Diego, La Jolla, California.
authors: Yuko
authors: Y
authors: Kono
authors: SignalRx Pharmaceuticals, San Diego, California.
authors: Joseph R
authors: JR
authors: Garlich
authors: SignalRx Pharmaceuticals, San Diego, California.
authors: Guillermo A
authors: GA
authors: Morales
authors: Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California. ddurden@ucsd.edu.|SignalRx Pharmaceuticals, San Diego, California.|Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, University of California San Diego Health System, La Jolla, California.
authors: Donald L
authors: DL
authors: Durden
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016259:Genes, myc; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D024363:Transcription Initiation Site; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002867:Chromones; D009536:Niacinamide; D009687:Nuclear Proteins; D009842:Oligopeptides; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D048490:raf Kinases; D018631:ras Proteins; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C526549:SF 1126