2. Academic Validation
  3. Discovery of the First Selective Nanomolar Inhibitors of ERAP2 by Kinetic Target-Guided Synthesis

Discovery of the First Selective Nanomolar Inhibitors of ERAP2 by Kinetic Target-Guided Synthesis

  • Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202203560. doi: 10.1002/anie.202203560.
Virgyl Camberlein 1 2,  Charlotte Fléau 1 2,  Pierre Sierocki 1 2,  Lenong Li 3,  Ronan Gealageas 1 2,  Damien Bosc 1 2,  Valentin Guillaume 1 2,  Sandrine Warenghem 1 2,  Florence Leroux 1 2,  Melissa Rosell 1 2,  Keguang Cheng 1 2,  Laura Medve 1 2,  Mathilde Prigent 1 2,  Myriam Decanter 1 2,  Catherine Piveteau 1 2,  Alexandre Biela 1 2,  Maxime Eveque 1 2,  Julie Dumont 1 2,  Anastasia Mpakali 4,  Petros Giastas 4,  Adrien Herledan 1 2,  Cyril Couturier 1 2,  Jörg Haupenthal 5,  Laetitia Lesire 1 2,  Anna K H Hirsch 5 6,  Benoit Deprez 1 2,  Efstratios Stratikos 4 7,  Marlene Bouvier 3,  Rebecca Deprez-Poulain 1 2
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, 3 rue du Pr Laguesse, 59000, Lille, France.
  • 2 European Genomic Institute for Diabetes, EGID, Pôle Recherche, 1 place de Verdun, 59045, Lille Cedex, France.
  • 3 Department of Microbiology and Immunology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL 60612, USA.
  • 4 National Center for Scientific Research Demokritos, Agia Paraskevi, 15341, Greece.
  • 5 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus E8 1, 66123, Saarbrücken, Germany.
  • 6 Department for Pharmacy, Saarland University, Campus E8 1, 66123, Saarbrücken, Germany.
  • 7 Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zographou, 15784, Greece.
PMID: 35904863 DOI: 10.1002/anie.202203560
Abstract

Endoplasmic reticulum Aminopeptidase 2 (ERAP2) is a key enzyme involved in the trimming of antigenic peptides presented by Major Histocompatibility Complex class I. It is a target of growing interest for the treatment of autoimmune diseases and in Cancer Immunotherapy. However, the discovery of potent and selective ERAP2 inhibitors is highly challenging. Herein, we have used kinetic target-guided synthesis (KTGS) to identify such inhibitors. Co-crystallization experiments revealed the binding mode of three different inhibitors with increasing potency and selectivity over related Enzymes. Selected analogues engage ERAP2 in cells and inhibit antigen presentation in a cellular context. 4 d (BDM88951) displays favorable in vitro ADME properties and in vivo exposure. In summary, KTGS allowed the discovery of the first nanomolar and selective highly promising ERAP2 inhibitors that pave the way of the exploration of the biological roles of this enzyme and provide lead compounds for drug discovery efforts.

Keywords

ERAP2; Isoform Selectivity; Medicinal Chemistry; Metalloenzymes; Protein-Templated Reactions.

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