title: Identification of 2-[4-[(4-Methoxyphenyl)methoxy]-phenyl]acetonitrile and Derivatives as Potent Oct3/4 Inducers.
abstract: 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.
authors.affiliation: †Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Xinlai
authors.initials: X
authors.lastname: Cheng
authors.affiliation: †Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Dimou
authors.affiliation: †Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Hamed
authors.initials: H
authors.lastname: Alborzinia
authors.affiliation: ‡Experimentelle Nephrologie, KIM III, Universitätsklinikum Jena, Am Nonnenplan 2-4, D-07743 Jena, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Wenke
authors.affiliation: ‡Experimentelle Nephrologie, KIM III, Universitätsklinikum Jena, Am Nonnenplan 2-4, D-07743 Jena, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Göhring
authors.affiliation: ‡Experimentelle Nephrologie, KIM III, Universitätsklinikum Jena, Am Nonnenplan 2-4, D-07743 Jena, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Reuter
authors.affiliation: §Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mah
authors.affiliation: ∥Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: §Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.affiliation: ∥Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
authors.affiliation: ⊥European Screening Port GmbH, Hamburg, Germany.
authors.forename: Sheraz
authors.initials: S
authors.lastname: Gul
authors.affiliation: #Center for Stroke Research Berlin, Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.affiliation: ∇Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg University, Mannheim, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
authors.affiliation: ○Theoretical Biophysics, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Edda
authors.initials: E
authors.lastname: Klipp
authors.affiliation: ‡Experimentelle Nephrologie, KIM III, Universitätsklinikum Jena, Am Nonnenplan 2-4, D-07743 Jena, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Mrowka
authors.affiliation: †Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
mesh_terms: D000097:Acetonitriles / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C000601138:2-(4-((4-methoxyphenyl)methoxy)phenyl)acetonitrile; D000097:Acetonitriles; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D010647:Phenyl Ethers