2. Academic Validation
  3. Discovery of New Nanomolar Selective IRAP Inhibitors

Discovery of New Nanomolar Selective IRAP Inhibitors

  • J Med Chem. 2025 Feb 27;68(4):4168-4195. doi: 10.1021/acs.jmedchem.4c01744.
Ben He 1,  Nour Bou Karroum 1,  Ronan Gealageas 1,  François-Xavier Mauvais 2 3,  Sandrine Warenghem 1,  Matthieu Roignant 1,  Nicolas Kraupner 1,  Bao Vy Lam 1,  Nathalie Azaroual 4,  Vincent Ultré 5,  Alexandre Rech 5,  Laetitia Lesire 1,  Cyril Couturier 1,  Florence Leroux 1 6,  Peter van Endert 2 7,  Benoit Deprez 1 6,  Rebecca Deprez-Poulain 1 6
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.
  • 2 Institut Necker Enfants Malades, Université Paris Cité, INSERM, CNRS, Paris F-75015, France.
  • 3 Service de Physiologie─Explorations Fonctionnelles, AP-HP, Hôpital Robert-Debré, Paris F-75019, France.
  • 4 University Lille, CHU Lille, ULR 7365─GRITA─Groupe de Recherche Sur Les Formes Injectables Et Les Technologies Associées, Lille F-59000, France.
  • 5 University Lille, Plateau RMN Pharmacie, UFR3S-Pharmacie, Lille F-59000, France.
  • 6 European Genomic Institute for Diabetes, EGID, University of Lille, Lille F-59000, France.
  • 7 Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, Paris F-75015, France.
PMID: 39916550 DOI: 10.1021/acs.jmedchem.4c01744
Abstract

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.

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