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Chemical modification of a synthetic small molecule boosts its biological efficacy against pluripotency genes in mouse fibroblasts.

Authors
Type
Published Article
Journal
ChemMedChem
1860-7187
Publisher
Wiley Blackwell (John Wiley & Sons)
Publication Date
Volume
9
Issue
10
Pages
2374–2380
Identifiers
DOI: 10.1002/cmdc.201402117
PMID: 25044886
Source
Medline
Keywords
  • Biological Activity
  • Cellular Uptake
  • Gene Expression
  • Polyamides
  • Transcription

Abstract

A synthetic transcriptional activator encompassing both sequence-specific pyrrole-imidazole polyamides (PIPs) and an epigenetic activator (suberoylanilide hydroxamic acid) was recently shown to induce the endogenous expression of core pluripotency genes in mouse embryonic fibroblasts (MEFs). Microarray data analysis suggested Oct-3/4 as the probable target pathway of the activator. However, the expression levels in MEFs treated with the activator were relatively lower than those in mouse embryonic stem cells. Herein, we report studies carried out to improve the efficacy of the activator and show that the biological activity was significantly (p<0.05) improved against the core pluripotency genes after the incorporation of an isophthalic acid (IPA) at the C terminus. The resultant IPA conjugate dramatically induced Oct-3/4 and demonstrated a new chemical strategy for developing PIP conjugates as next-generation genetic switches.

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