An αv-RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities

There is a requirement for efficacious and safe medicines to treat diseases with high unmet need. The resurgence in alpha nu-RGD integrin inhibitor drug discovery is poised to contribute to this requirement. However, drug discovery in the alpha nu integrin space is notoriously difficult due to the receptors being structurally very similar as well as the polar zwitterionic nature of the pharmacophore. This Review aims to guide drug discovery research in this field through an alpha nu inhibitor toolbox, consisting of small molecules and antibodies. Small-molecule v tool compounds with extended profiles in alpha nu beta 1, 3, 5, 6 and 8 cell adhesion assays, with key physicochemical properties, have been collated to assist in the selection of the right tool for the right experiment. This should also facilitate an understanding of partial selectivity profiles of compounds generated in different assays across research institutions. Prospects for further alpha nu integrin research and the critical importance of target validation are discussed, where increased knowledge of the selectivity for individual RGD alpha nu integrins is key. Insights into the design of small-molecule RGD chemotypes for topical or oral administration are provided and clinical findings on advanced molecules are examined.