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  • Review Article
  • Published:

Integrins as therapeutic targets: lessons and opportunities

Key Points

  • Integrins are widely expressed cell-adhesion molecules with key roles in thrombosis, inflammation and cancer, and as a result are important drug targets.

  • Inhibitors of αIIbβ3, α4 and αLβ2 integrins have been approved for the treatment of thrombosis, multiple sclerosis and psoriasis.

  • The α4 and αLβ2 integrin inhibitors are associated with fatal progressive multifocal leukoencephalopathy, whereas the orally active αIIbβ3 integrin inhibitors are associated with increased cardiovascular mortality.

  • These adverse events were unexpected owing to the lack of understanding of the role of integrins in cell signalling.

  • Recent advances in understanding the structure of integrins and their signalling pathways provide the possibility of developing new classes of integrin inhibitors with improved pharmacological profiles.

Abstract

The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets.

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Figure 1: Integrin families.
Figure 2: Integrin structure and changes upon activation.
Figure 3: Structure and function of integrin α-I and β-I domains.
Figure 4: Integrin activation states and inhibitor sites.
Figure 5: Structural analysis of inhibitors of integrins.

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Supplementary information S1 (figure)

Analysis of the lengths of β3 antagonists (PDF 562 kb)

Supplementary information S2 (figure)

Structural overlay of the binding pocket of αIIbβ3 and αVβ3 (PDF 1204 kb)

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Glossary

Rossmann fold

A protein structural motif consisting of at least three β sheets linked by α helices in an alternating manner. They are found in nucleotide-binding proteins and integrin interactive domains.

π–π stacking interaction

π–π interactions are especially important in the interaction between hydrophobic ring structures including those in tyrosines and phenylalanines. They occur when the delocalized electrons in the p-orbitals of π-conjugated systems are shared between two stacked ring structures.

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Cox, D., Brennan, M. & Moran, N. Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov 9, 804–820 (2010). https://doi.org/10.1038/nrd3266

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