Emerging therapeutic opportunities for integrin inhibitors

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins alpha IIb beta 3, alpha 4 beta 7/alpha 4 beta 1 and alpha L beta 2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of alpha v integrins, including alpha v beta 3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins alpha v beta 6 and alpha v beta 1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the alpha v integrins. Integrins are key signalling molecules that are present on the surface of subsets of cells and are therefore good potential therapeutic targets. In this Review, Hatley and colleagues discuss the development of integrin inhibitors, particularly the challenges in developing inhibitors for integrins that contain an alpha v-subunit, and suggest how these challenges could be addressed.