Discovery of pyrimidine-based small activators of insulin degrading enzyme

  • Eur J Med Chem. 2026 May 5:309:118740. doi: 10.1016/j.ejmech.2026.118740.
Jamal El Bakali  1 ,  Cyril Ronco  1 ,  Valérie Landry  1 ,  Konstantinos D Papavasileiou  2 ,  Michail Papadourakis  2 ,  Sandrine Warenghem  1 ,  Florence Leroux  3 ,  Julie Charton  1 ,  Julie Dumont  1 ,  Catherine Piveteau  1 ,  Bart Staels  4 ,  Antreas Afantitis  5 ,  Nathalie Hennuyer  4 ,  Benoit Deprez  6 ,  Damien Bosc  1 ,  Rebecca Deprez-Poulain  7
Affiliations
  • 1. Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, Lille, F-59000, France.
  • 2. Novamechanics Ltd., Nicosia, 1516, Cyprus.
  • 3. Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, Lille, F-59000, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France.
  • 4. Univ. Lille, Inserm, Institut Pasteur de Lille, U1011 - Nuclear Receptors, Metabolic & Cardiovascular Diseases, Lille, F-59000, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France.
  • 5. Novamechanics Ltd., Nicosia, 1516, Cyprus; Department of Pharmacy, Frederick University, Nicosia, 1036, Cyprus.
  • 6. Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, Lille, F-59000, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France. Electronic address: [email protected].
  • 7. Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, Lille, F-59000, France; European Genomic Institute for Diabetes, EGID, University of Lille, F-59000, France. Electronic address: [email protected].
PMID: 41864041 DOI: 10.1016/j.ejmech.2026.118740
Abstract

Insulin-Degrading Enzyme IDE, a zinc metalloprotease that has been associated with Alzheimer 's disease, metabolic diseases and Cancer, is an attractive target. Its complex structure, substrate preferences, non-catalytic activities require the development of modulators of this enzyme. While several potent inhibitors are now available, we still lack activators for both in vitro and in vivo explorations of IDE functions and potential application in Alzheimer 's disease. Here we describe the discovery of an original pyrimidine-based series of IDE activators by screening and its structure-activity relationships. Docking studies suggest that compounds may bind the IDE dimer interface, and sterically increase IDE catalytic activity. In vitro and in vivo activities of best activator are consistent with an increase in Insulin hydrolysis by IDE in the presence of the activator BDM71230. This compound can serve as a pharmacological tool to explore this intriguing enzyme.

Keywords
Activators; Enzymes; Metalloproteases; Screening.
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