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

Autor: Virgyl Camberlein, Charlotte Fléau, Pierre Sierocki, Lenong Li, Ronan Gealageas, Damien Bosc, Valentin Guillaume, Sandrine Warenghem, Florence Leroux, Melissa Rosell, Keguang Cheng, Laura Medve, Mathilde Prigent, Myriam Decanter, Catherine Piveteau, Alexandre Biela, Maxime Eveque, Julie Dumont, Anastasia Mpakali, Petros Giastas, Adrien Herledan, Cyril Couturier, Jörg Haupenthal, Laetitia Lesire, Anna K. H. Hirsch, Benoit Deprez, Efstratios Stratikos, Marlene Bouvier, Rebecca Deprez‐Poulain
Rok vydání: 2022
Předmět:
Zdroj: Angewandte Chemie. 134
ISSN: 1521-3757
0044-8249
Popis: 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.
Databáze: OpenAIRE
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