Identification of potent inhibitors of the sortilin-progranulin interaction

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 17; p. 127403
• Main 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.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2020; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Progranulin; Protein-protein interaction inhibitor; Science & Technology; Sortilin; Structure activity relationship; Protein-protein interaction inhibitor; Structure activity relationship; Progranulin; Sortilin; PROTEIN
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127403

[Display omitted] 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.