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

19 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 2016

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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

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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, 11.2016, p. 2553-2562.

Research output: Contribution to journalArticle

Singh, AR, Joshi, S, Burgoyne, AM, Sicklick, JK, Ikeda, S, Kono, Y, Garlich, JR, Morales, GA & Durden, DL 2016, 'Single agent and synergistic activity of the "first-in-class" dual PI3K/BRD4 inhibitor SF1126 with sorafenib in hepatocellular carcinoma', Molecular cancer therapeutics, vol. 15, no. 11, pp. 2553-2562. https://doi.org/10.1158/1535-7163.MCT-15-0976
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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