Single agent and synergistic activity of the "first-in-class" dual PI3K/BRD4 inhibitor SF1126 with sorafenib in hepatocellular carcinoma

Alok R. Singh, Shweta Joshi, Adam M. Burgoyne, Jason K. Sicklick, Sadakatsu Ikeda, Yuko Kono, Joseph R. Garlich, Guillermo A. Morales, Donald L Durden

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2553-2562
Number of pages10
JournalMolecular cancer therapeutics
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Hepatocellular Carcinoma
Cell Line
Phase II Clinical Trials
Clinical Trials, Phase I
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Prodrugs
sorafenib
SF 1126
Histones
Chromatin
Cell Cycle
Proteins
Apoptosis
Safety
Enzymes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Single agent and synergistic activity of the "first-in-class" dual PI3K/BRD4 inhibitor SF1126 with sorafenib in hepatocellular carcinoma. / Singh, Alok R.; Joshi, Shweta; Burgoyne, Adam M.; Sicklick, Jason K.; Ikeda, Sadakatsu; Kono, Yuko; Garlich, Joseph R.; Morales, Guillermo A.; Durden, Donald L.

In: Molecular cancer therapeutics, Vol. 15, No. 11, 01.11.2016, p. 2553-2562.

Research output: Contribution to journalArticle

Singh, Alok R. ; Joshi, Shweta ; Burgoyne, Adam M. ; Sicklick, Jason K. ; Ikeda, Sadakatsu ; Kono, Yuko ; Garlich, Joseph R. ; Morales, Guillermo A. ; Durden, Donald L. / Single agent and synergistic activity of the "first-in-class" dual PI3K/BRD4 inhibitor SF1126 with sorafenib in hepatocellular carcinoma. In: Molecular cancer therapeutics. 2016 ; Vol. 15, No. 11. pp. 2553-2562.
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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.",
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AU - Singh, Alok R.

AU - Joshi, Shweta

AU - Burgoyne, Adam M.

AU - Sicklick, Jason K.

AU - Ikeda, Sadakatsu

AU - Kono, Yuko

AU - Garlich, Joseph R.

AU - Morales, Guillermo A.

AU - Durden, Donald L

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AB - 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.

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