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
  • 1. Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: [email protected].
  • 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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