BibTex format
@article{Wilkinson:2021:10.1016/j.ejphar.2021.174618,
author = {Wilkinson, AL and John, AE and Barrett, JW and Gower, E and Morrison, VS and Man, Y and Pun, KT and Roper, JA and Luckett, JC and Borthwick, LA and Barksby, BS and Burgoyne, RA and Barnes, R and Fisher, AJ and Procopiou, PA and Hatley, RJD and Barrett, TN and Marshall, RP and Macdonald, SJF and Jenkins, RG and Slack, RJ},
doi = {10.1016/j.ejphar.2021.174618},
journal = {European Journal of Pharmacology},
pages = {1--10c},
title = {Pharmacological characterisation of GSK3335103, an oral alpha v beta 6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease},
url = {http://dx.doi.org/10.1016/j.ejphar.2021.174618},
volume = {913},
year = {2021}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ) via the alpha-V beta-6 (αvβ6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvβ6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvβ6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvβ6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvβ6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvβ6 integrin and inhibit the activation of TGFβ in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvβ6 engagement, TGFβ signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvβ6 inhibitor that attenuates TGFβ signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders.
AU - Wilkinson,AL
AU - John,AE
AU - Barrett,JW
AU - Gower,E
AU - Morrison,VS
AU - Man,Y
AU - Pun,KT
AU - Roper,JA
AU - Luckett,JC
AU - Borthwick,LA
AU - Barksby,BS
AU - Burgoyne,RA
AU - Barnes,R
AU - Fisher,AJ
AU - Procopiou,PA
AU - Hatley,RJD
AU - Barrett,TN
AU - Marshall,RP
AU - Macdonald,SJF
AU - Jenkins,RG
AU - Slack,RJ
DO - 10.1016/j.ejphar.2021.174618
EP - 10
PY - 2021///
SN - 0376-6357
SP - 1
TI - Pharmacological characterisation of GSK3335103, an oral alpha v beta 6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease
T2 - European Journal of Pharmacology
UR - http://dx.doi.org/10.1016/j.ejphar.2021.174618
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000752130000002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR - https://www.sciencedirect.com/science/article/pii/S0014299921007743?via%3Dihub
VL - 913
ER -