Discovery of New Nanomolar Selective IRAP Inhibitors
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 <b>43</b> (<b>BDM_92499</b>), 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.
Authors
- Ronan Gealageas (ORCID: https://orcid.org/0000-0003-2105-1993)
- François‐Xavier Mauvais (ORCID: https://orcid.org/0000-0002-5240-4280)
- Laëtitia Lesire (ORCID: https://orcid.org/0000-0003-1019-5182)
- Rebecca Deprez‐Poulain (ORCID: https://orcid.org/0000-0002-3318-5297)
- Matthieu Roignant
- Alexandre Rech
- Ben He (ORCID: https://orcid.org/0009-0000-8530-8618)
- Peter Van Endert (ORCID: https://orcid.org/0000-0003-3782-0750)
- Cyril Couturier (ORCID: https://orcid.org/0000-0002-6840-1738)
- Vincent Ultré
- Florence Leroux (ORCID: https://orcid.org/0000-0003-0554-873X)
- Sandrine Warenghem (ORCID: https://orcid.org/0000-0001-9113-6058)
- Nicolas Kraupner (ORCID: https://orcid.org/0000-0002-2440-2624)
- Nour Bou Karroum (ORCID: https://orcid.org/0000-0002-1516-9090)
- Benoit P. Deprez (ORCID: https://orcid.org/0000-0002-2777-4538)
- Bao Vy Lam (ORCID: https://orcid.org/0000-0002-5713-4507)
- Nathalie Azaroual
Institutions
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Institut Necker Enfants Malades (FR)
- Sorbonne Paris Cité (FR)
- Hôpital Robert-Debré (FR)
- Pharmac (NZ)
- Living Systems (United States) (US)
- European Genomic Institute for Diabetes (FR)
- Médicaments et Molécules pour Agir sur les Systèmes Vivants
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01744
- Citations
- 2
- Primary Topic
- Neuropeptides and Animal Physiology
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- Université de Lille
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Conseil Régional Hauts-de-France
- H2020 Marie Skłodowska-Curie Actions