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Pharmacological characterisation of GSK3335103, an oral αvβ6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease

Lookup NU author(s): Dr Lee Borthwick, Ben Barksby, Rachel Burgoyne, Rory Barnes, Professor Andrew FisherORCiD


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© 2021 Elsevier B.V.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.

Publication metadata

Author(s): Wilkinson AL, John AE, Barrett JW, Gower E, Morrison VS, Man Y, Pun KT, Roper JA, Luckett JC, Borthwick LA, Barksby BS, Burgoyne RA, Barnes R, Fisher AJ, Procopiou PA, Hatley RJD, Barrett TN, Marshall RP, Macdonald SJF, Jenkins RG, Slack RJ

Publication type: Article

Publication status: Published

Journal: European Journal of Pharmacology

Year: 2021

Volume: 913

Print publication date: 15/12/2021

Online publication date: 08/11/2021

Acceptance date: 03/11/2021

ISSN (print): 0014-2999

ISSN (electronic): 1879-0712

Publisher: Elsevier B.V.


DOI: 10.1016/j.ejphar.2021.174618


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