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Discovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and In Silico Studies.

ABSTRACT: 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.

SUBMITTER: Deddouche-Grass S

PROVIDER: S-EPMC8274102 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Discovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and <i>In Silico</i> Studies.

Deddouche-Grass Safia S Andouche Cyrielle C Bärenz Felix F Halter Célia C Hohwald Arnaud A Lebrun Louison L Membré Nathalie N Morales Renaud R Muzet Nicolas N Poirot Matthieu M Reynaud Morgane M Roujean Véronique V Weber Fabienne F Zimmermann André A Heng Rama R Basse Nicolas N

ACS medicinal chemistry letters 20210604 7

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 f ...[more]

PMID: 34267884

Dataset Information

Discovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and In Silico Studies.

Publications

Discovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and <i>In Silico</i> Studies.

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