Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

John, Alison E.; Graves, Rebecca H.; Pun, K. Tao; Vitulli, Giovanni; Forty, Ellen; Mercer, Paul F.; Morrell, Josie; Barrett, John W.; Rogers, Rebecca; Hafeji, Maryam; Bibby, Lloyd I.; Gower, Elaine; Morrison, Valerie S.; Man, Yim; Roper, James A.; Luckett, Jeni; Borthwick, Lee A.; Barksby, Ben S.; Burgoyne, Rachel A.; Barnes, Rory; Le, Joelle; Flint, David; Pyne, Susan; Habgood, Anthony; Organ, Louise; Joseph, Chitra; Edwards-Pritchard, Rochelle C.; Maher, Toby M.; Fisher, Andrew J.; Gudmann, N.S.; Leeming, Diana Julie; Chambers, Rachel C.; Lukey, Pauline T.; Marshall, Richard P.; Macdonald, Simon J. F.; Jenkins, R Gisli; Slack, Robert J.

doi:10.1038/s41467-020-18397-6

Cited by 89 publications

(87 citation statements)

References 46 publications

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“…It has been clinically tested in several cancer indications ( 184 , 185 ), and proved safe, but did not achieve a survival benefit. Very recently, the integrin αvβ6 inhibitor GSK3008348 has been shown to have an effect on lung fibrosis in a mouse therapeutic model ( 220 ).…”

Section: Discussionmentioning

confidence: 99%

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

et al. 2021

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The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.

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Section: Discussionmentioning

confidence: 99%

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

et al. 2021

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“…Some anti‐TGF‐β approaches have been evaluated as monotherapies in animal models of fibrosis and limited clinical studies to target fibrosis‐associated conditions. Multiple studies illustrate the abilities of neutralizing anti‐TGF‐β antibodies and TGF‐β receptor kinase inhibitors to prevent fibrosis in preclinical models of lung, liver, heart, and kidney fibrosis, to the extent that they are often used as positive controls in the evaluation of novel approaches to inhibit fibrosis [186] or validation of novel research models [187,188]. For example, vactosertib prevents or attenuates fibrosis in liver fibrosis models upon carbon tetrachloride injury or bile duct ligation, bleomycin‐induced lung fibrosis, and renal fibrosis following unilateral ureteral obstruction [189].…”

Section: Therapeutic Approaches Toward Inhibition Of Tgf‐β In Fibrosismentioning

confidence: 99%

TGF‐β as a driver of fibrosis: physiological roles and therapeutic opportunities

Budi

Schaub

Decaris

et al. 2021

The Journal of Pathology

146

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Many chronic diseases are marked by fibrosis, which is defined by an abundance of activated fibroblasts and excessive deposition of extracellular matrix, resulting in loss of normal function of the affected organs. The initiation and progression of fibrosis are elaborated by pro‐fibrotic cytokines, the most critical of which is transforming growth factor‐β1 (TGF‐β1). This review focuses on the fibrogenic roles of increased TGF‐β activities and underlying signaling mechanisms in the activated fibroblast population and other cell types that contribute to progression of fibrosis. Insight into these roles and mechanisms of TGF‐β as a universal driver of fibrosis has stimulated the development of therapeutic interventions to attenuate fibrosis progression, based on interference with TGF‐β signaling. Their promise in preclinical and clinical settings will be discussed. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…The αvβ6 targeting antibody BG00011 is currently evaluated in a phase IIa clinical study for idiopathic pulmonary fibrosis (NCT03573505) [ 110 ]. An αvβ6-targeting RGD-mimetic, GSK3008348, was recently published as novel, highly selective, and affine αvβ6 ligand with anti-fibrotic therapeutic potential [ 475 , 476 , 477 ]. GSK300834 reduced downstream pro-fibrotic TGF-β signaling to normal levels by rapid internalization and lysosomal degradation of αvβ6.…”

Section: Integrin Targeting In Non-cancer Diseasesmentioning

confidence: 99%

“…GSK300834 reduced downstream pro-fibrotic TGF-β signaling to normal levels by rapid internalization and lysosomal degradation of αvβ6. In a bleomycin-induced murine lung fibrosis model, GSK300834 was used as an inhalable therapeutic and reduced lung collagen deposition and fibrosis progression [ 475 ]. The results of a small phase Ib study (eight patients) indicate that nebulized dosing with GSK300834 was safe and led to successful target engagement [ 478 ].…”

Section: Integrin Targeting In Non-cancer Diseasesmentioning

confidence: 99%

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

Ludwig

Kessler

Kossatz

et al. 2021

Cancers

144

116

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Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet the high expectations yet, integrins are still valid and promising targets due to their elevated expression and surface accessibility on diseased cells. Thus, for the future successful clinical translation of integrin-targeted compounds, revisited and innovative treatment strategies have to be explored based on accumulated knowledge of integrin biology. For this, refined approaches are demanded aiming at alternative and improved preclinical models, optimized selectivity and pharmacological properties of integrin ligands, as well as more sophisticated treatment protocols considering dose fine-tuning of compounds. Moreover, integrin ligands exert high accuracy in disease monitoring as diagnostic molecular imaging tools, enabling patient selection for individualized integrin-targeted therapy. The present review comprehensively analyzes the state-of-the-art knowledge on the roles of RGD-binding integrin subtypes in cancer and non-cancerous diseases and outlines the latest achievements in the design and development of synthetic ligands and their application in biomedical, translational, and molecular imaging approaches. Indeed, substantial progress has already been made, including advanced ligand designs, numerous elaborated pre-clinical and first-in-human studies, while the discovery of novel applications for integrin ligands remains to be explored.

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Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

Cited by 89 publications

References 46 publications

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

TGF‐β as a driver of fibrosis: physiological roles and therapeutic opportunities

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

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