title: Ethyl 2-((4-Chlorophenyl)amino)thiazole-4-carboxylate and Derivatives Are Potent Inducers of Oct3/4.
abstract: The octamer-binding transcription factor 4 (Oct3/4) is a master gene in the transcriptional regulatory network of pluripotent cells. Repression of Oct3/4 in embryonic stem cells (ESCs) is associated with cell differentiation and loss of pluripotency, whereas forced overexpression in cooperation with other transcriptional factors, such as Nanog, Sox2, and Lin28, can reprogram somatic cells back into pluripotent cells, termed induced pluripotent stem cells (iPSCs). However, random integration and potential tumorigenic transformation caused by viral transduction limit the clinical application of iPSCs. By performing a cell-based high throughput screening (HTS) campaign, we identified several potential small molecules as inducers of Oct3/4 expression. Here we report a lead structure ethyl 2-((4-chlorophenyl)amino)-thiazole-4-carboxylate, termed O4I2, showing high activity in enforcing Oct3/4 expression. On the basis of chemical expansion, we further identified derivatives having increased activities toward Oct3/4 induction. Thus, O4I2 and its derivatives should provide a new class of small molecules suitable for iPSC generation.
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: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: †Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Dena
authors.initials: D
authors.lastname: Raoofi
authors.affiliation: †Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Sawsan
authors.initials: S
authors.lastname: Saleh
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, 13125 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, 40225 Duesseldorf, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: §Max Delbrück Center for Molecular Medicine, 13125 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, 40225 Duesseldorf, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
authors.affiliation: ⊥European Screening Port GmbH, 22525 Hamburg, Germany.
authors.forename: Sheraz
authors.initials: S
authors.lastname: Gul
authors.affiliation: #Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
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: D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D013844:Thiazoles; C000603358:ethyl 2-((4-chlorophenyl)amino)thiazole-4-carboxylate