2. Academic Validation
  3. Identification of potent inhibitors of the sortilin-progranulin interaction

Identification of potent inhibitors of the sortilin-progranulin interaction

  • Bioorg Med Chem Lett. 2020 Sep 1;30(17):127403. doi: 10.1016/j.bmcl.2020.127403.
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
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: shawn_stachel@merck.com.
  • 2 Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • 3 Department of Chemistry and Structural Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • 4 Department of Neuroscience, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • 5 Department of Pharmacology, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • 6 Screening and Protein Science, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
PMID: 32738972 DOI: 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.

Keywords

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

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