Identification of potent inhibitors of the sortilin-progranulin interaction. Issue 17 (1st September 2020)

• Record Type: Journal Article
• Authors: Stachel, Shawn J.; Ginnetti, Anthony T.; Johnson, Scott A.; Cramer, Paige; Wang, Yi; Bukhtiyarova, Marina; Krosky, Daniel; Stump, Craig; Hurzy, Danielle M.; Schlegel, Kelly-Ann; Cooke, Andrew J.; Allen, Samantha; O'Donnell, Gregory; Ziebell, Michael; Parthasarathy, Gopal; Getty, Krista L.; Ho, Thu; Ou, Yangsi; Jovanovska, Aneta; Carroll, Steve S.; Pausch, Mark; Lumb, Kevin; Mosser, Scott D.; Voleti, Bhavya; Klein, Daniel J.; Soisson, Stephen M.; Zerbinatti, Celina; Coleman, Paul J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 17(2020)
• Publication Date: 2020-09-01
• Subjects: Sortilin -- Progranulin -- Protein-protein interaction inhibitor -- Structure activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127403
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.