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
  • 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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