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Ethyl 2-((4-Chlorophenyl)amino)thiazole-4-carboxylate and derivatives are potent inducers of Oct3/4

: Cheng, X.; Yoshida, H.; Raoofi, D.; Saleh, S.; Alborzinia, H.; Wenke, F.; Göhring, A.; Reuter, S.; Mah, N.; Fuchs, H.; Andrade-Navarro, M.A.; Adjaye, J.; Gul, S.; Utikal, J.; Mrowka, R.; Wölfl, S.


Journal of medicinal chemistry 58 (2015), No.15, pp.5742-5750
ISSN: 0022-2623
ISSN: 1520-4804
Journal Article
Fraunhofer IME ()

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 h aving increased activities toward Oct3/4 induction. Thus, O4I2 and its derivatives should provide a new class of small molecules suitable for iPSC generation.