Identification of indole-based activators of insulin degrading enzyme

Nicolas Kraupner (1) , Chau Phi Dinh (1) , Xiaoan Wen (1) , Valérie Landry (1) , Adrien Herledan (1) , Florence Leroux (1, 2) , Damien Bosc (1) , Julie Charton (1, 2) , Clara Maillard (1) , Sandrine Warenghem (1) , Isabelle Duplan (3, 2) , Catherine Piveteau (1) , Nathalie Hennuyer (3, 2) , Bart Staels (3, 2) , Benoit Deprez (1, 2) , Rebecca Deprez-Poulain (1, 2)

1 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
2 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
3 RNMCD - Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011

Insulin degrading enzyme (IDE) is a zinc metalloprotease that cleaves numerous substrates among which amyloid-β and insulin. It has been linked through genetic studies to the risk of type-2 diabetes (T2D) or Alzheimer's disease (AD). Pharmacological activation of IDE is an attractive therapeutic strategy in AD. While IDE inhibition gave paradoxal activity in glucose homeostasis, recent studies, in particular in the liver suggest that IDE activators could be also of interest in diabetes. Here we describe the discovery of an original series of IDE activators by screening and structure-activity relationships. Early cellular studies show that hit 1 decreases glucose-stimulating insulin secretion. Docking studies revealed it has an unprecedented extended binding to the polyanion-binding site of IDE. These indole-based pharmacological tools are activators of both Aβ and insulin hydrolysis by IDE and could be helpful to explore the multiple roles of IDE.

Mots clés: Insulin-degrading enzyme; Activators; Screening; Metalloenzymes

Domaines: Sciences pharmaceutiques

Nicolas Kraupner, Chau Phi Dinh, Xiaoan Wen, Valérie Landry, Adrien Herledan, et al.. Identification of indole-based activators of insulin degrading enzyme. European Journal of Medicinal Chemistry, 2021, pp.113982. ⟨10.1016/j.ejmech.2021.113982⟩. ⟨hal-03430475⟩