Pharmacological characterisation of GSK3335103, an oral v6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease

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-beta (TGF beta) via the alpha-V beta-6 (alpha v beta 6) 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 alpha v beta 6 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 alpha v beta 6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of alpha v beta 6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the alpha v beta 6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the alpha v beta 6 integrin and inhibit the activation of TGF beta in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by alpha v beta 6 engagement, TGF beta signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent alpha v beta 6 inhibitor that attenuates TGF beta 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.