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

François Béliveau; Aarti Tarkar; Sébastien P Dion; Antoine Désilets; Mariana Gabriela Ghinet; Pierre-Luc Boudreault; Catherine St-Georges; Éric Marsault; Daniel Paone; Jon Collins; Colin H Macphee; Nino Campobasso; Arthur Groy; Josh Cottom; Michael Ouellette; Andrew J Pope; Richard Leduc

doi:10.1016/j.chembiol.2019.09.004

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

Cell Chem Biol. 2019 Nov 21;26(11):1559-1572.e9. doi: 10.1016/j.chembiol.2019.09.004. Epub 2019 Sep 19.

Authors

François Béliveau¹, Aarti Tarkar², Sébastien P Dion¹, Antoine Désilets¹, Mariana Gabriela Ghinet¹, Pierre-Luc Boudreault¹, Catherine St-Georges¹, Éric Marsault¹, Daniel Paone², Jon Collins², Colin H Macphee², Nino Campobasso³, Arthur Groy³, Josh Cottom³, Michael Ouellette³, Andrew J Pope², Richard Leduc⁴

Affiliations

¹ Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12(e) Avenue Nord, Sherbrooke, QC J1H 5N4, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
² Discovery Partnerships with Academia, GlaxoSmithKline, Collegeville, Philadelphia, PA 19426-0989, USA.
³ Platform Technology & Science, GlaxoSmithKline, Collegeville, Philadelphia, PA 19426-0989, USA.
⁴ Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12(e) Avenue Nord, Sherbrooke, QC J1H 5N4, Canada; Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address: richard.leduc@usherbrooke.ca.

PMID: 31543462
DOI: 10.1016/j.chembiol.2019.09.004

Abstract

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 peptidomimetic 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 hepatocytes, we show that TMPRSS6 inhibitors block TMPRSS6-dependent hemojuvelin cleavage and increase HAMP expression and levels of secreted hepcidin.

Keywords: HAMP; HJV; TMPRSS6; hepcidin; iron regulation; matriptase-2; serine protease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzothiazoles / chemistry
Binding Sites
Catalytic Domain
Cell Survival / drug effects
Drug Evaluation, Preclinical*
GPI-Linked Proteins / metabolism
Hemochromatosis Protein / metabolism
Hep G2 Cells
Hepatocytes / cytology
Hepatocytes / metabolism
Hepcidins / metabolism*
High-Throughput Screening Assays
Humans
Iron / metabolism
Membrane Proteins / antagonists & inhibitors*
Membrane Proteins / metabolism
Molecular Dynamics Simulation
Peptidomimetics
Proteolysis / drug effects
Serine Endopeptidases / chemistry
Serine Endopeptidases / metabolism
Serine Proteinase Inhibitors / chemistry*
Serine Proteinase Inhibitors / metabolism
Serine Proteinase Inhibitors / pharmacology
Up-Regulation / drug effects

Substances

Benzothiazoles
GPI-Linked Proteins
HAMP protein, human
HJV protein, human
Hemochromatosis Protein
Hepcidins
Membrane Proteins
Peptidomimetics
Serine Proteinase Inhibitors
Iron
Serine Endopeptidases
TMPRSS6 protein, human
matriptase
benzothiazole

Grants and funding

CIHR/Canada