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iScience. 2019 Feb 22;12:168-181. doi: 10.1016/j.isci.2019.01.012. Epub 2019 Jan 11.

Imidazopyridines as Potent KDM5 Demethylase Inhibitors Promoting Reprogramming Efficiency of Human iPSCs.

Author information

1
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, ImNeuenheimer Feld 364, 69120 Heidelberg, Germany.
2
Faculty of Biology, University Mainz, Gresemundweg 2, 55128 Mainz, Germany; Institute of Molecular Biology GmbH, Ackermannweg 4, 55128 Mainz, Germany.
3
Experimentelle Nephrologie, KIM III, Universitätsklinikum, 07743 Jena, Germany.
4
Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University, 40225 Düsseldorf, Germany.
5
Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany.
6
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510275, China.
7
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, ImNeuenheimer Feld 364, 69120 Heidelberg, Germany. Electronic address: x.cheng@uni-heidelberg.de.

Abstract

Pioneering human induced pluripotent stem cell (iPSC)-based pre-clinical studies have raised safety concerns and pinpointed the need for safer and more efficient approaches to generate and maintain patient-specific iPSCs. One approach is searching for compounds that influence pluripotent stem cell reprogramming using functional screens of known drugs. Our high-throughput screening of drug-like hits showed that imidazopyridines-analogs of zolpidem, a sedative-hypnotic drug-are able to improve reprogramming efficiency and facilitate reprogramming of resistant human primary fibroblasts. The lead compound (O4I3) showed a remarkable OCT4 induction, which at least in part is due to the inhibition of H3K4 demethylase (KDM5, also known as JARID1). Experiments demonstrated that KDM5A, but not its homolog KDM5B, serves as a reprogramming barrier by interfering with the enrichment of H3K4Me3 at the OCT4 promoter. Thus our results introduce a new class of KDM5 chemical inhibitors and provide further insight into the pluripotency-related properties of KDM5 family members.

KEYWORDS:

Biochemistry; Biological Sciences; Molecular Biology

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