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. 2020 Sep 1;30(17):127403.
doi: 10.1016/j.bmcl.2020.127403. Epub 2020 Jul 15.

Identification of potent inhibitors of the sortilin-progranulin interaction

Shawn J Stachel  1 , Anthony T Ginnetti  2 , Scott A Johnson  3 , Paige Cramer  4 , Yi Wang  5 , Marina Bukhtiyarova  5 , Daniel Krosky  5 , Craig Stump  2 , Danielle M Hurzy  2 , Kelly-Ann Schlegel  2 , Andrew J Cooke  2 , Samantha Allen  5 , Gregory O'Donnell  6 , Michael Ziebell  6 , Gopal Parthasarathy  3 , Krista L Getty  6 , Thu Ho  6 , Yangsi Ou  5 , Aneta Jovanovska  5 , Steve S Carroll  5 , Mark Pausch  5 , Kevin Lumb  6 , Scott D Mosser  5 , Bhavya Voleti  4 , Daniel J Klein  3 , Stephen M Soisson  3 , Celina Zerbinatti  4 , Paul J Coleman  2
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Identification of potent inhibitors of the sortilin-progranulin interaction

Shawn J Stachel et al. Bioorg Med Chem Lett. .

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.

Keywords: Progranulin; Protein-protein interaction inhibitor; Sortilin; Structure activity relationship.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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