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Identification of 2-[4-[(4-methoxyphenyl)methoxy]-phenyl]acetonitrile and derivatives as potent Oct3/4 inducers

Item Type:Article
Title:Identification of 2-[4-[(4-methoxyphenyl)methoxy]-phenyl]acetonitrile and derivatives as potent Oct3/4 inducers
Creators Name:Cheng, X. and Dimou, E. and Alborzinia, H. and Wenke, F. and Goehring, A. and Reuter, S. and Mah, N. and Fuchs, H. and Andrade-Navarro, M.A. and Adjaye, J. and Gul, S. and Harms, C. and Utikal, J. and Klipp, E. and Mrowka, R. and Woelfl, S.
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.
Keywords:Acetonitriles, Cultured Cells, Drug Discovery, HEK293 Cells, Molecular Models, Octamer Transcription Factor-3, Phenyl Ethers, Up-Regulation
Source:Journal of Medicinal Chemistry
ISSN:0022-2623
Publisher:American Chemical Society (U.S.A.)
Volume:58
Number:12
Page Range:4976-4983
Date:25 June 2015
Official Publication:https://doi.org/10.1021/acs.jmedchem.5b00144
PubMed:View item in PubMed

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