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. Epub 2020 Jul 15.

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.

MeSH terms

  • Adaptor Proteins, Vesicular Transport / antagonists & inhibitors
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amides / chemistry
  • Amides / metabolism
  • Amino Acids / chemistry
  • Amino Acids / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • High-Throughput Screening Assays
  • Humans
  • Molecular Dynamics Simulation
  • Progranulins / antagonists & inhibitors
  • Progranulins / metabolism*
  • Protein Binding
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Structure-Activity Relationship

Substances

  • Adaptor Proteins, Vesicular Transport
  • Amides
  • Amino Acids
  • Progranulins
  • Pyrazoles
  • Small Molecule Libraries
  • sortilin