2014 Fiscal Year Final Research Report
Small Bioactive Molecules for Orchestrating Embryonic Stem Cell Differentiation
Project/Area Number |
25870365
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Chemical biology
Developmental biology
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Research Institution | Kyoto University |
Principal Investigator |
PERRON AMELIE 京都大学, 化学研究所, 講師 (40525862)
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Project Period (FY) |
2013-04-01 – 2015-03-31
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Keywords | SAR Studies / Hes1 / Regenerative Medicine / Stem Cells / Oscillations / Microarray / Transcription / Gro/TLE |
Outline of Final Research Achievements |
a) Screening and SAR studies: Using a transcriptional assay, we isolated 3 hits from an indole-containing chemical library of 1800 small molecules. D8C was validated as a Hes1 modulator as it was able to inhibit Hes1-mediated repression. 176 derivatives were synthetized and tested to optimize D8C. JI051 showed a 10-fold improvement as compared to D8C. b) Effect on Oscillations: Presomitic mesoderm preparations showed a decrease in Hes7 oscillations upon treatment with JI051. c) Target Validation Procedure: Pull-down assays revealed a band corresponding to Gro/TLE. However, competition with 10-fold excess of JI051 was partially successful, suggesting that TLE1 may not be the sole target. 211 kinases were tested to investigate if kinases involved in Gro/TLE corepressor activity, could be modulated by JI051. No inhibition or stimulation higher than 50% was shown. Microarray analysis to identify other potential targets revealed an up-regulation of several genes involved in hypoxia.
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Free Research Field |
small organic molecules
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