Identification of potent inhibitors of the sortilin-progranulin interaction

Shawn J. Stachel, Anthony T. Ginnetti, Scott A. Johnson, Paige Cramer, Yi Wang, Marina Bukhtiyarova, Daniel Krosky, Craig Stump, Danielle M. Hurzy, Kelly Ann Schlegel, Andrew J. Cooke, Samantha Allen, Gregory O'Donnell, Michael Ziebell, Gopal Parthasarathy, Krista L. Getty, Thu Ho, Yangsi Ou, Aneta Jovanovska, Steve S. CarrollMark Pausch, Kevin Lumb, Scott D. Mosser, Bhavya Voleti, Daniel J. Klein, Stephen M. Soisson, Celina Zerbinatti, Paul J. Coleman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number127403
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number17
DOIs
StatePublished - Sep 1 2020
Externally publishedYes

Keywords

  • Progranulin
  • Protein-protein interaction inhibitor
  • Sortilin
  • Structure activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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