Identification of potent inhibitors of the sortilin-progranulin interaction.

Identification of potent inhibitors of the sortilin-progranulin interaction.
Bioorg Med Chem Lett. 2020 Sep 01;30(17):127403
Authors: Stachel SJ, Ginnetti AT, Johnson SA, Cramer P, Wang Y, Bukhtiyarova M, Krosky D, Stump C, Hurzy DM, Schlegel KA, Cooke AJ, Allen S, O'Donnell G, Ziebell M, Parthasarathy G, Getty KL, Ho T, Ou Y, Jovanovska A, Carroll SS, Pausch M, Lumb K, Mosser SD, Voleti B, Klein DJ, Soisson SM, Zerbinatti C, Coleman PJ
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.
PMID: 32738972 [PubMed - in process]

Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Stachel SJ, Ginnetti AT, Johnson SA, Cramer P, Wang Y, Bukhtiyarova M, Krosky D, Stump C, Hurzy DM, Schlegel KA, Cooke AJ, Allen S, O'Donnell G, Ziebell M, Parthasarathy G, Getty KL, Ho T, Ou Y, Jovanovska A, Carroll SS, Pausch M, Lumb K, Mosser SD, Volet Tags: Bioorg Med Chem Lett Source Type: research