| Autor: |
Liddle J; Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Hutchinson JP; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Kitchen S; Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Rowland P; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Neu M; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Cecconie T; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States., Holmes DS; Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Jones E; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Korczynska J; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Koumantou D; National Centre for Scientific Research 'Demokritos', Patriarchou Gregoriou and Neapoleos 27, Agia Paraskevi, Athens 15341, Greece., Lea JD; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Nickels L; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States., Pemberton M; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Phillipou A; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Schneck JL; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States., Sheehan H; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Tinworth CP; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Uings I; Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Wojno-Picon J; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Young RJ; Medicinal Science and Technology, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K., Stratikos E; National Centre for Scientific Research 'Demokritos', Patriarchou Gregoriou and Neapoleos 27, Agia Paraskevi, Athens 15341, Greece. |
| Abstrakt: |
ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates antigenic peptides and is an emerging target for cancer immunotherapy and the control of autoimmunity. ERAP1 inhibitors described previously target the active site and are limited in selectivity, minimizing their clinical potential. To address this, we targeted the regulatory site of ERAP1 using a high-throughput screen and discovered a small molecule hit that is highly selective for ERAP1. (4a R ,5 S ,6 R ,8 S ,8a R )-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid is a natural product found in Dodonaea viscosa that constitutes a submicromolar, highly selective, and cell-active modulator of ERAP1. Although the compound activates hydrolysis of small model substrates, it is a competitive inhibitor for physiologically relevant longer peptides. Crystallographic analysis confirmed that the compound targets the regulatory site of the enzyme that normally binds the C-terminus of the peptide substrate. Our findings constitute a novel starting point for the development of selective ERAP1 modulators that have potential for further clinical development. |
