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

Autor: Wilkinson AL; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., John AE; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Cale Street, London, UK., Barrett JW; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Gower E; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Morrison VS; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Man Y; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Pun KT; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Roper JA; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Luckett JC; Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, UK., Borthwick LA; Fibrosis Research Group, Newcastle University Biosciences Institute, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, UK., Barksby BS; Fibrosis Research Group, Newcastle University Biosciences Institute, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, UK., Burgoyne RA; Fibrosis Research Group, Newcastle University Biosciences Institute, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, UK., Barnes R; Fibrosis Research Group, Newcastle University Biosciences Institute, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, UK., Fisher AJ; Fibrosis Research Group, Newcastle University Biosciences Institute, Newcastle University Translational and Clinical Research Institute, Newcastle Upon Tyne, UK; Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS, Foundation Trust, Newcastle Upon Tyne, UK., Procopiou PA; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Hatley RJD; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Barrett TN; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Marshall RP; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Macdonald SJF; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK., Jenkins RG; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Cale Street, London, UK., Slack RJ; Fibrosis DPU, Respiratory TAU, GlaxoSmithKline, Stevenage, Hertfordshire, UK. Electronic address: RJSlack@galecto.com.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2021 Dec 15; Vol. 913, pp. 174618. Date of Electronic Publication: 2021 Nov 08.
DOI: 10.1016/j.ejphar.2021.174618
Abstrakt: 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.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: