Year: 2025
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Among the M1 family of oxytocinase aminopeptidases, insulin-regulated aminopeptidase IRAP, is an emerging drug target implicated in various biological pathways and particularly in MHC-I antigen presentation through amino-terminal trimming of exogenous cross-presented peptides. A few series of inhibitors inspired either by angiotensin IV, one of IRAP substrates, or by bestatin a pan aminopeptidase inhibitor, have been disclosed. However, the variety and number of chemotypes remains relatively limited. Here we disclose the design and optimization of a series of hydroxamic acids IRAP inhibitors bearing a 5-substituted indole. Docking studies of the best compound 43 ( BDM_92499 ), a single-digit nanomolar and selective inhibitor of IRAP, suggest an original binding mode and highlight the substituent on the indole and a primary amide as groups driving selectivity. Several inhibitors in the series displayed IRAP-dependent inhibition of antigen cross-presentation. These results pave the way to the development of novel therapeutic agents targeting IRAP.
Source: Journal of Medicinal Chemistry
Authors: Ben He, Nour Bou Karroum, Ronan Gealageas, François-Xavier Mauvais, Sandrine Warenghem, Matthieu Roignant, Nicolas Kraupner, Bao Vy Lam, Nathalie Azaroual, Vincent Ultré, Alexandre Rech, Laetitia Lesire, Cyril Couturier, Florence Leroux, Peter van Endert, Benoit Deprez, Rebecca Deprez-Poulain
Institutions: Inserm, Université de Lille, Institut Pasteur de Lille, Médicaments et Molécules pour Agir sur les Systèmes Vivants, Hôpital Necker-Enfants Malades, Centre National de la Recherche Scientifique, Université Paris Cité, Institut Necker Enfants Malades, Assistance Publique – Hôpitaux de Paris, Hôpital Robert-Debré, Centre Hospitalier Universitaire de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées, European Genomic Institute for Diabetes
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: Training experts in antigen processing to deliver new drug prototypes for cancer and autoimmune diseases, ERAP inhibitors as a new approach to treat autoimmune & autoinflammatory diseases, G3976661348, EGID Diabetes Pole, Training experts in antigen processing to deliver new drug prototypes for cancer and autoimmune diseases, G6011114603
OpenAlex ID: W4407259194