Casein kinase 1δ/ε inhibitor, PF670462 attenuates the fibrogenic effects of transforming growth factor-β in pulmonary fibrosis

Christine R. Keenan, Shenna Y. Langenbach, Fernando Jativa, Trudi Harris, Meina Li, Qianyu Chen, Yuxiu Xia, Bryan Gao, Michael J. Schuliga, Jade Jaffar, Danica Prodanovic, Yan Tu, Asres Berhan, Peter V.S. Lee, Glen P. Westall, Alastair G. Stewart

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Abstract

Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a 'therapeutic' regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.

Original languageEnglish
Article number738
Number of pages15
JournalFrontiers in Pharmacology
Volume9
Issue numberJUL
DOIs
Publication statusPublished - 10 Jul 2018

Keywords

  • Anti-fibrotic
  • Collagen
  • Epithelial mesenchymal transition
  • Lung
  • Mechanobiology
  • Myofibroblast
  • PF-670462
  • TGF-β

Cite this

Keenan, Christine R. ; Langenbach, Shenna Y. ; Jativa, Fernando ; Harris, Trudi ; Li, Meina ; Chen, Qianyu ; Xia, Yuxiu ; Gao, Bryan ; Schuliga, Michael J. ; Jaffar, Jade ; Prodanovic, Danica ; Tu, Yan ; Berhan, Asres ; Lee, Peter V.S. ; Westall, Glen P. ; Stewart, Alastair G. / Casein kinase 1δ/ε inhibitor, PF670462 attenuates the fibrogenic effects of transforming growth factor-β in pulmonary fibrosis. In: Frontiers in Pharmacology. 2018 ; Vol. 9, No. JUL.
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abstract = "Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a 'therapeutic' regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.",
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author = "Keenan, {Christine R.} and Langenbach, {Shenna Y.} and Fernando Jativa and Trudi Harris and Meina Li and Qianyu Chen and Yuxiu Xia and Bryan Gao and Schuliga, {Michael J.} and Jade Jaffar and Danica Prodanovic and Yan Tu and Asres Berhan and Lee, {Peter V.S.} and Westall, {Glen P.} and Stewart, {Alastair G.}",
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Keenan, CR, Langenbach, SY, Jativa, F, Harris, T, Li, M, Chen, Q, Xia, Y, Gao, B, Schuliga, MJ, Jaffar, J, Prodanovic, D, Tu, Y, Berhan, A, Lee, PVS, Westall, GP & Stewart, AG 2018, 'Casein kinase 1δ/ε inhibitor, PF670462 attenuates the fibrogenic effects of transforming growth factor-β in pulmonary fibrosis', Frontiers in Pharmacology, vol. 9, no. JUL, 738. https://doi.org/10.3389/fphar.2018.00738

Casein kinase 1δ/ε inhibitor, PF670462 attenuates the fibrogenic effects of transforming growth factor-β in pulmonary fibrosis. / Keenan, Christine R.; Langenbach, Shenna Y.; Jativa, Fernando; Harris, Trudi; Li, Meina; Chen, Qianyu; Xia, Yuxiu; Gao, Bryan; Schuliga, Michael J.; Jaffar, Jade; Prodanovic, Danica; Tu, Yan; Berhan, Asres; Lee, Peter V.S.; Westall, Glen P.; Stewart, Alastair G.

In: Frontiers in Pharmacology, Vol. 9, No. JUL, 738, 10.07.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Casein kinase 1δ/ε inhibitor, PF670462 attenuates the fibrogenic effects of transforming growth factor-β in pulmonary fibrosis

AU - Keenan, Christine R.

AU - Langenbach, Shenna Y.

AU - Jativa, Fernando

AU - Harris, Trudi

AU - Li, Meina

AU - Chen, Qianyu

AU - Xia, Yuxiu

AU - Gao, Bryan

AU - Schuliga, Michael J.

AU - Jaffar, Jade

AU - Prodanovic, Danica

AU - Tu, Yan

AU - Berhan, Asres

AU - Lee, Peter V.S.

AU - Westall, Glen P.

AU - Stewart, Alastair G.

PY - 2018/7/10

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N2 - Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a 'therapeutic' regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.

AB - Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a 'therapeutic' regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.

KW - Anti-fibrotic

KW - Collagen

KW - Epithelial mesenchymal transition

KW - Lung

KW - Mechanobiology

KW - Myofibroblast

KW - PF-670462

KW - TGF-β

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U2 - 10.3389/fphar.2018.00738

DO - 10.3389/fphar.2018.00738

M3 - Article

VL - 9

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

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