Identification of 2-[4-[(4-Methoxyphenyl)methoxy]-phenyl]acetonitrile and Derivatives as Potent Oct3/4 Inducers
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- 作者：Xinlai Cheng ; Eleni Dimou ; Hamed Alborzinia ; Frank Wenke ; Axel G枚hring ; Stefanie Reuter ; Nancy Mah ; Heiko Fuchs ; Miguel A. Andrade-Navarro ; James Adjaye ; Sheraz Gul ; Christoph Harms ; Jochen Utikal ; Edda Klipp ; Ralf Mrowka ; Stefan W枚lfl
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 25, 2015
- 年：2015
- 卷：58
- 期：12
- 页码：4976-4983
- 全文大小：381K
- ISSN：1520-4804
文摘
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.