Compelling validation studies demonstrating the role of αv integrins in diseases with high unmet medical need continues to build. Historically, clinical trials mainly targeted αvβ3 for cancer, osteoporosis and rheumatoid arthritis, but translation to a marketed drug has not yet come to fruition. There has recently been a resurgence in integrin research, now directed at the TGFβ pathway – mediated by αvβ1 and αvβ6 integrins – mostly for treating fibrotic diseases in multiple organs, such as, idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Several new chemotypes have entered clinical trials. We give a brief overview of key αv-inhibitors (biologics, peptides, small molecules) in the context of physical properties, selectivity profiles and clinical outcomes. The design of small molecule αv-inhibitors continues to be centred on the RGD tripeptide integrin recognition sequence. However, we highlight that mimicking all the residues of RGD is not always required for activity and may advantageously provide novel chemotypes with differentiated properties. Here, this approach was used in the identification and design of new, potent and selective αvβ1 inhibitors. Hit finding through a focussed screen provided non-RGD start points of legacy α4β1 antagonists containing unexpected αvβ1 activity. The use of in silico calculations and docking studies enabled the properties to be optimized for αvβ1, where incorporation of a non-basic urea motif modulated the binding in the αv-subunit. Overall, the high synthetic tractability and excellent selectivity of the urea lead series demonstrates the validity of this approach, which could have potential application to the other αv integrins. It serves as an excellent start point for future optimization and for use in studies to investigate fibrotic diseases.

αv-Integrin inhibitors to combat cancer and fibrosis: Past, present and future

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.