|059P London, UK
Discovery of a novel, high affinity, small molecule alpha-v beta-6 integrin inhibitor for the treatment of idiopathic pulmonary fibrosis
Introduction: Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality in disorders that include idiopathic pulmonary fibrosis (IPF). The alpha-v beta-6 (αvβ6) integrin has been identified as playing a key role in the activation of transforming growth factor-β (TGFβ) that is hypothesised to be pivotal in the development of IPF . Therefore, a drug discovery programme within GlaxoSmithKline to identify small molecule αvβ6 selective RGD-mimetics was initiated.
Method: As part of a medicinal chemistry programme GSK3008348  was identified and profiled in a range of pre-clinical in vitro (radioligand binding , flow cytometry , functional TGFβ  and high content screening assays) and in vivo (bleomycin-induced lung injury mouse model (20 and 60 IU bleomycin treated male C57/Bl6 mice)) systems.
Results: GSK3008348 (1% DMSO) was shown to bind to the αvβ6 with high affinity (pKD 11.3ą0.07, meanąSEM, n=6 donors) in membrane preparations generated from IPF human lung tissue. In primary human lung epithelial cells GSK3008348 (0.1% DMSO) induced rapid internalisation of αvβ6 (t1/22.6ą0.5 min, meanąSEM, n=4) followed by a slow return of the integrin to the cell surface (t1/2 11.0ą1.9 h, meanąSEM, n=4). It was shown that αvβ6 is degraded in lysosomes post-internalisation by GSK3008348 that would suggest the slow return of integrin to the surface and sustained duration of action is a consequence of new αvβ6 synthesis. GSK3008348 (1 mg/kg i.n. saline) was shown to engage with αvβ6 and inhibit the activation of TGFβ with a prolonged duration of action using in vivo mouse bleomycin lung fibrosis models measuring αvβ6 engagement (SPECT imaging ) and TGFβ signalling (pSMAD2 lung levels).
Conclusion: In summary, GSK3008348 displays the desirable pharmacological characteristics required for targeting a prolonged inhibition of TGFβ activation in the IPF lung via blockade of the αvβ6 integrin and is currently in Phase I trials for IPF .
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