Identification of a Novel Deactivating Small-Molecule Compound for Fibrogenic Hepatic Stellate Cells

Yonago Acta Medica
Takuki SakaguchiGoshi Shiota

Abstract

Liver fibrosis progresses to decompensated liver cirrhosis, for which medical needs remain unmet. We recently developed IC-2, a small-molecule compound that suppresses Wnt/β-catenin signaling, and found that IC-2 also suppresses liver fibrosis. In this study, we performed three-step screening of newly synthesized IC-2 derivatives to identify other small-molecule compounds that suppress liver fibrosis. The screening system consisted of three steps: a cell viability assay, a transcription factor 4 (TCF4) reporter assay, and induction of α-smooth muscle actin (α-SMA) and collagen 1α1 (Col1A1) expression in response to each compound. Screening using human LX-2 hepatic stellate cells (HSCs) was performed to target HSCs, which are the driver cells of liver fibrosis. In the first step, since 9b and 9b-CONH2 at 100 μM did not have any effects on cell viability, they were omitted in the next screening. Additionally, the conditions that led to > 40% inhibition of the controls were also excluded in subsequent screening. The second step was performed under 31 conditions for 19 small-molecule compounds. Sixteen small-molecule compounds caused significant reduction of TCF4 activity relative to that of 0.1% DMSO. Of the 16 compounds, the 10 s...Continue Reading

References

Nov 3, 2005·Nature Clinical Practice. Gastroenterology & Hepatology·Scott L Friedman
Jul 14, 2007·Hepatology Research : the Official Journal of the Japan Society of Hepatology·Takashi ShimomuraGoshi Shiota
Sep 22, 2007·American Journal of Physiology. Gastrointestinal and Liver Physiology·Yoko YoshidaGoshi Shiota
Nov 17, 2007·American Journal of Physiology. Gastrointestinal and Liver Physiology·Jason H ChengHidekazu Tsukamoto
Jan 11, 2013·Science Translational Medicine·Scott L FriedmanShelia Violette
Feb 1, 2014·Lancet·Emmanuel A TsochatzisAndrew K Burroughs
Mar 10, 2015·Gastroenterology·Satdarshan Pal Monga
May 17, 2017·Advanced Drug Delivery Reviews·Takaaki HigashiYujin Hoshida

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