Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

Alison E. John; Rebecca H. Graves; Tao Pun; Giovanni Vitulli; Ellen J. Forty; Paul F. Mercer; Josie L. Morrell; John W. Barrett; Rebecca F. Rogers; Maryam Hafeji; Lloyd I. Bibby; Elaine Gower; Valerie S. Morrison; Yim Man; James A. Roper; Jeni C. Luckett; Lee A. Borthwick; Ben S. Barksby; Rachel A. Burgoyne; Rory  Barnes; Joelle Le; David J. Flint; Susan Pyne; Anthony Habgood; Louise A. Organ; Chitra Joseph; Rochelle C. Edwards-Pritchard; Toby M. Maher; Andrew J. Fisher; Natasja Staehr Gudmann; Diana J. Leeming; Rachel C. Chambers; Pauline T. Lukey; Richard P. Marshall; Simon J. F. Macdonald; Gisli Jenkins; Robert J. Slack

doi:10.1038/s41467-020-18397-6

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

Alison E. John, Rebecca H. Graves, Tao Pun, Giovanni Vitulli, Ellen J. Forty, Paul F. Mercer, Josie L. Morrell, John W. Barrett, Rebecca F. Rogers, Maryam Hafeji, Lloyd I. Bibby, Elaine Gower, Valerie S. Morrison, Yim Man, James A. Roper, Jeni C. Luckett, Lee A. Borthwick, Ben S. Barksby, Rachel A. Burgoyne, Rory BarnesJoelle Le, David J. Flint, Susan Pyne, Anthony Habgood, Louise A. Organ, Chitra Joseph, Rochelle C. Edwards-Pritchard, Toby M. Maher, Andrew J. Fisher, Natasja Staehr Gudmann, Diana J. Leeming, Rachel C. Chambers, Pauline T. Lukey, Richard P. Marshall, Simon J. F. Macdonald, Gisli Jenkins, Robert J. Slack

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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Abstract

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human
IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

Original language	English
Article number	4659
Number of pages	14
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18397-6
Publication status	Published - 16 Sept 2020

Keywords

idiopathic pulmonary fibrosis
lung epithelial cells
abnormal wound healing

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John, A. E., Graves, R. H., Pun, T., Vitulli, G., Forty, E. J., Mercer, P. F., Morrell, J. L., Barrett, J. W., Rogers, R. F., Hafeji, M., Bibby, L. I., Gower, E., Morrison, V. S., Man, Y., Roper, J. A., Luckett, J. C., Borthwick, L. A., Barksby, B. S., Burgoyne, R. A., ... Slack, R. J. (2020). Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis. Nature Communications, 11(1), Article 4659. https://doi.org/10.1038/s41467-020-18397-6

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title = "Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis",

abstract = "The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in humanIPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.",

keywords = "idiopathic pulmonary fibrosis, lung epithelial cells, abnormal wound healing",

author = "John, {Alison E.} and Graves, {Rebecca H.} and Tao Pun and Giovanni Vitulli and Forty, {Ellen J.} and Mercer, {Paul F.} and Morrell, {Josie L.} and Barrett, {John W.} and Rogers, {Rebecca F.} and Maryam Hafeji and Bibby, {Lloyd I.} and Elaine Gower and Morrison, {Valerie S.} and Yim Man and Roper, {James A.} and Luckett, {Jeni C.} and Borthwick, {Lee A.} and Barksby, {Ben S.} and Burgoyne, {Rachel A.} and Rory Barnes and Joelle Le and Flint, {David J.} and Susan Pyne and Anthony Habgood and Organ, {Louise A.} and Chitra Joseph and Edwards-Pritchard, {Rochelle C.} and Maher, {Toby M.} and Fisher, {Andrew J.} and Gudmann, {Natasja Staehr} and Leeming, {Diana J.} and Chambers, {Rachel C.} and Lukey, {Pauline T.} and Marshall, {Richard P.} and Macdonald, {Simon J. F.} and Gisli Jenkins and Slack, {Robert J.}",

year = "2020",

month = sep,

day = "16",

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John, AE, Graves, RH, Pun, T, Vitulli, G, Forty, EJ, Mercer, PF, Morrell, JL, Barrett, JW, Rogers, RF, Hafeji, M, Bibby, LI, Gower, E, Morrison, VS, Man, Y, Roper, JA, Luckett, JC, Borthwick, LA, Barksby, BS, Burgoyne, RA, Barnes, R, Le, J, Flint, DJ, Pyne, S, Habgood, A, Organ, LA, Joseph, C, Edwards-Pritchard, RC, Maher, TM, Fisher, AJ, Gudmann, NS, Leeming, DJ, Chambers, RC, Lukey, PT, Marshall, RP, Macdonald, SJF, Jenkins, G & Slack, RJ 2020, 'Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis', Nature Communications, vol. 11, no. 1, 4659. https://doi.org/10.1038/s41467-020-18397-6

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T1 - Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

AU - John, Alison E.

AU - Graves, Rebecca H.

AU - Pun, Tao

AU - Vitulli, Giovanni

AU - Forty, Ellen J.

AU - Mercer, Paul F.

AU - Morrell, Josie L.

AU - Barrett, John W.

AU - Rogers, Rebecca F.

AU - Hafeji, Maryam

AU - Bibby, Lloyd I.

AU - Gower, Elaine

AU - Morrison, Valerie S.

AU - Man, Yim

AU - Roper, James A.

AU - Luckett, Jeni C.

AU - Borthwick, Lee A.

AU - Barksby, Ben S.

AU - Burgoyne, Rachel A.

AU - Barnes, Rory

AU - Le, Joelle

AU - Flint, David J.

AU - Pyne, Susan

AU - Habgood, Anthony

AU - Organ, Louise A.

AU - Joseph, Chitra

AU - Edwards-Pritchard, Rochelle C.

AU - Maher, Toby M.

AU - Fisher, Andrew J.

AU - Gudmann, Natasja Staehr

AU - Leeming, Diana J.

AU - Chambers, Rachel C.

AU - Lukey, Pauline T.

AU - Marshall, Richard P.

AU - Macdonald, Simon J. F.

AU - Jenkins, Gisli

AU - Slack, Robert J.

PY - 2020/9/16

Y1 - 2020/9/16

N2 - The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in humanIPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

AB - The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in humanIPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

KW - idiopathic pulmonary fibrosis

KW - lung epithelial cells

KW - abnormal wound healing

U2 - 10.1038/s41467-020-18397-6

DO - 10.1038/s41467-020-18397-6

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4659

ER -

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

Abstract

Keywords

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