학술논문
Discovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and In Silico Studies.
Document Type
Academic Journal
Author
Deddouche-Grass S; Sanofi, 67080 Strasbourg, France.; Andouche C; Sanofi, 67080 Strasbourg, France.; Bärenz F; Sanofi, D-65926 Frankfurt am Main, Germany.; Halter C; Domain Therapeutics, 67400 Illkirch, France.; Hohwald A; Sanofi, 67080 Strasbourg, France.; Lebrun L; Domain Therapeutics, 67400 Illkirch, France.; Membré N; Sanofi, 67080 Strasbourg, France.; Morales R; Sanofi, 67080 Strasbourg, France.; Muzet N; Sanofi, 67080 Strasbourg, France.; Poirot M; Sanofi, 67080 Strasbourg, France.; Reynaud M; Biosynex, 67400 Illkirch, France.; Roujean V; Sanofi, 67080 Strasbourg, France.; Weber F; Sanofi, 67080 Strasbourg, France.; Zimmermann A; Sanofi, 67080 Strasbourg, France.; Heng R; Evotec, 31036 Toulouse cedex, France.; Basse N; Sanofi, 67080 Strasbourg, France.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1948-5875
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.
Competing Interests: The authors declare no competing financial interest.
(© 2021 American Chemical Society.)
Competing Interests: The authors declare no competing financial interest.
(© 2021 American Chemical Society.)