Identification of potent inhibitors of the sortilin-progranulin interaction.

Reference

Stachel, S., Ginnetti, A., Johnson, M., Cramer, P., Wang, L., Bukhtiyarova, M., Krosky, D., Stump, C., Hurzy, D., Schlegel, K.-A., Cooke, A., Allen, S., O’Donnell, G., Ziebell, M., Parthasarathy, G., Getty, K., Ho, T., Ou, Y., Jovanovska, A., … Coleman, P. (2020). Identification of potent inhibitors of the sortilin-progranulin interaction. 30(17). https://doi.org/10.1016/j.bmcl.2020.127403

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.