Open AccessDiscovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and In Silico Studies
Author(s) -
Safia Deddouche-Grass,
Cyrielle Andouche,
Felix Bärenz,
Célia Halter,
Arnaud Hohwald,
Louison Lebrun,
Nathalie Membré,
Renaud Morales,
Nicolas Muzet,
Matthieu Poirot,
Morgane Reynaud,
Véronique Roujean,
Fabienne A. Weber,
André Zimmermann,
Rama Heng,
Nicolas Basse
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00235
Subject(s) - in silico , adme , computational biology , single nucleotide polymorphism , potency , snp , chemistry , pharmacology , biology , gene , biochemistry , in vitro , genotype
ERAP1 is a key aminopeptidase involved in peptide trimming before major histocompatibility complex (MHC) presentation. A single nucleotide polymorphism (SNP) in the ERAP1 gene can lead to impaired trimming activity and affect ERAP1 function. ERAP1 genetic variations have been linked to an increased susceptibility to cancer and autoimmune disease. Here, we report the discovery of novel ERAP1 inhibitors using a high throughput screening approach. Due to ERAP1 broad substrate specificity, the hit finding strategy included testing inhibitors with a range of biochemical assays. Based on the hit potency, selectivity, and in vitro absorption, distribution, metabolism, excretion, and toxicity, the benzofuran series was selected. Fifteen derivatives were designed and synthesized, the compound potency was improved to the nanomolar range, and the structure-activity relationship supported by modeling studies.