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J Med Chem. 2015 Jun 25;58(12):4976-83. doi: 10.1021/acs.jmedchem.5b00144. Epub 2015 May 7.

Identification of 2-[4-[(4-Methoxyphenyl)methoxy]-phenyl]acetonitrile and Derivatives as Potent Oct3/4 Inducers.

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†Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
‡Experimentelle Nephrologie, KIM III, Universitätsklinikum Jena, Am Nonnenplan 2-4, D-07743 Jena, Germany.
§Max Delbrück Center for Molecular Medicine, Berlin, Germany.
∥Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
⊥European Screening Port GmbH, Hamburg, Germany.
#Center for Stroke Research Berlin, Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
∇Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg University, Mannheim, Germany.
○Theoretical Biophysics, Humboldt-Universität zu Berlin, Berlin, Germany.


Reprogramming somatic cells into induced-pluripotent cells (iPSCs) provides new access to all somatic cell types for clinical application without any ethical controversy arising from the use of embryonic stem cells (ESCs). Established protocols for iPSCs generation based on viral transduction with defined factors are limited by low efficiency and the risk of genetic abnormality. Several small molecules have been reported as replacements for defined transcriptional factors, but a chemical able to replace Oct3/4 allowing the generation of human iPSCs is still unavailable. Using a cell-based High Throughput Screening (HTS) campaign, we identified that 2-[4-[(4-methoxyphenyl)methoxy]phenyl]acetonitrile (1), termed O4I1, enhanced Oct3/4 expression. Structural verification and modification by chemical synthesis showed that O4I1 and its derivatives not only promoted expression and stabilization of Oct3/4 but also enhanced its transcriptional activity in diverse human somatic cells, implying the possible benefit from using this class of compounds in regenerative medicine.

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