Yes / The integrin family of cell surface extracellular matrix binding proteins are key to several physiological processes involved in tissue development, as well as cancer proliferation and dissemination. They are therefore attractive targets for drug discovery with cancer and non-cancer applications. We have developed a new integrin antagonist chemotype incorporating a functionalised cyclobutane ring as the central scaffold in an arginine–glycine–aspartic acid mimetic structure. Here, we report the synthesis of cyclobutanecarboxylic acids and cyclobutylamines with tetrahydronaphthyridine and aminopyridine arginine mimetic sidechains and masked carboxylic acid aspartic acid mimetic sidechains of varying length. Effective αvβ3 antagonists and new aspartic acid mimetics were identified in cell-based adhesion and invasion assays. A lead compound selected based on in vitro activity (IC50 < 1 μM), stability (t1/2 > 80 minutes) and synthetic tractability was well-tolerated in vivo. These results show the promise of this synthetic approach for developing αvβ3 antagonists and provide a firm foundation to progress into advanced preclinical evaluation prior to progression towards the clinic. Additionally, they highlight the use of functionalised cyclobutanes as metabolically stable core structures and a straightforward and robust method for their synthesis. This important contribution to the medicinal chemists' toolbox paves the way for increased use of cyclobutanes in drug discovery. / This work was funded by Yorkshire Cancer Research (Award reference number B002-PhD) and Prostate Cancer UK (Pilot Grant PA10-01).
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/20031 |
| Date | 24 August 2024 |
| Creators | Throup, Adam E., Zraikat, Manar Saleh Ali, Gordon, Andrew, Jafarinejad Soumehsaraei, S., Haase, K.D., Patterson, Laurence H., Cooper, Patricia A., Hanlon, K., Loadman, Paul, Sutherland, Mark, Shnyder, Steven, Sheldrake, Helen |
| Source Sets | Bradford Scholars |
| Language | English, English |
| Detected Language | English |
| Type | Article, Published version |
| Rights | This article is licensed under a Creative Commons Attribution 3.0 Unported Licence., CC-BY |
Page generated in 0.0021 seconds