@article{John:2020:10.1038/s41467-020-18397-6,
author = {John, AE and Graves, RH and Pun, KT and Vitulli, G and Forty, EJ and Mercer, PF and Morrell, JL and Barrett, JW and Rogers, RF and Hafeji, M and Bibby, LI and Gower, E and Morrison, VS and Man, Y and Roper, JA and Luckett, JC and Borthwick, LA and Barksby, BS and Burgoyne, RA and Barnes, R and Le, J and Flint, DJ and Pyne, S and Habgood, A and Organ, LA and Joseph, C and Edwards-Pritchard, RC and Maher, TM and Fisher, AJ and Gudmann, NS and Leeming, DJ and Chambers, RC and Lukey, PT and Marshall, RP and Macdonald, SJF and Jenkins, RG and Slack, RJ},
doi = {10.1038/s41467-020-18397-6},
journal = {Nature Communications},
title = {Translational pharmacology of an inhaled small molecule alpha v beta 6 integrin inhibitor for idiopathic pulmonary fibrosis},
url = {http://dx.doi.org/10.1038/s41467-020-18397-6},
volume = {11},
year = {2020}
}

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TY  - JOUR
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 disease-related 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.
AU  - John,AE
AU  - Graves,RH
AU  - Pun,KT
AU  - Vitulli,G
AU  - Forty,EJ
AU  - Mercer,PF
AU  - Morrell,JL
AU  - Barrett,JW
AU  - Rogers,RF
AU  - Hafeji,M
AU  - Bibby,LI
AU  - Gower,E
AU  - Morrison,VS
AU  - Man,Y
AU  - Roper,JA
AU  - Luckett,JC
AU  - Borthwick,LA
AU  - Barksby,BS
AU  - Burgoyne,RA
AU  - Barnes,R
AU  - Le,J
AU  - Flint,DJ
AU  - Pyne,S
AU  - Habgood,A
AU  - Organ,LA
AU  - Joseph,C
AU  - Edwards-Pritchard,RC
AU  - Maher,TM
AU  - Fisher,AJ
AU  - Gudmann,NS
AU  - Leeming,DJ
AU  - Chambers,RC
AU  - Lukey,PT
AU  - Marshall,RP
AU  - Macdonald,SJF
AU  - Jenkins,RG
AU  - Slack,RJ
DO  - 10.1038/s41467-020-18397-6
PY  - 2020///
SN  - 2041-1723
TI  - Translational pharmacology of an inhaled small molecule alpha v beta 6 integrin inhibitor for idiopathic pulmonary fibrosis
T2  - Nature Communications
UR  - http://dx.doi.org/10.1038/s41467-020-18397-6
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000573778500005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.nature.com/articles/s41467-020-18397-6
UR  - http://hdl.handle.net/10044/1/97027
VL  - 11
ER  - 

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