Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes

被引：26

作者：

Beliveau, Francois ^{[1
,2
]}

Tarkar, Aarti ^{[3
]}

Dion, Sebastien P. ^{[1
,2
]}

Desilets, Antoine ^{[1
,2
]}

Ghinet, Mariana Gabriela ^{[1
,2
]}

Boudreault, Pierre-Luc ^{[1
,2
]}

St-Georges, Catherine ^{[1
,2
]}

Marsault, Eric ^{[1
,2
]}

Paone, Daniel ^{[3
]}

Collins, Jon ^{[3
]}

Macphee, Colin H. ^{[3
]}

Campobasso, Nino ^{[4
]}

Groy, Arthur ^{[4
]}

Cottom, Josh ^{[4
]}

Ouellette, Michael ^{[4
]}

Pope, Andrew J. ^{[3
]}

Leduc, Richard ^{[1
,2
]}

机构：

[1] Univ Sherbrooke, Dept Pharmacol Physiol, Fac Med & Hlth Sci, 3001,12e Ave Nord, Sherbrooke, PQ J1H 5N4, Canada

[2] Univ Sherbrooke, Inst Pharmacol Sherbrooke, Sherbrooke, PQ, Canada

[3] GlaxoSmithKline, Discovery Partnerships Acad, Philadelphia, PA 19426 USA

[4] GlaxoSmithKline, Platform Technol & Sci, Philadelphia, PA 19426 USA

来源：

CELL CHEMICAL BIOLOGY | 2019年 / 26卷 / 11期

基金：

加拿大健康研究院;

关键词：

SERINE-PROTEASE MATRIPTASE-2; ENCODED LIBRARY TECHNOLOGY; BETA-THALASSEMIA; IRON OVERLOAD; HEREDITARY HEMOCHROMATOSIS; CLEAVAGE SITES; MOUSE MODEL; IDENTIFICATION; EXPRESSION; FERROPORTIN;

D O I：

10.1016/j.chembiol.2019.09.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Iron overload disorders are characterized by the body's inability to regulate iron absorption and its storage which can lead to organ failures. Accumulated evidence has revealed that hepcidin, the master regulator of iron homeostasis, is negatively modulated by TMPRSS6 (matriptase-2), a liver-specific type II transmembrane serine protease (TTSP). Here, we report that treatment with a pep-tidomimetic inhibitor affecting TMPRSS6 activity increases hepcidin production in hepatic cells. Moreover, similar effects were observed when using non-peptidic inhibitors obtained through optimization of hits from high-throughput screening. Using HepG2 cells and human primary hepato-cytes, we show that TMPRSS6 inhibitors block TMPRSS6- dependent hemojuvelin cleavage and increase HAMP expression and levels of secreted hepcidin.

引用

页码：1559 / +

页数：23

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