Abstract

Transcription factors GATA4 and NKX2-5 directly interact and synergistically activate several cardiac genes and stretch-induced cardiomyocyte hypertrophy. Previously, we identified phenylisoxazole carboxamide 1 as a hit compound, which inhibited the GATA4-NKX2-5 transcriptional synergy. Here, the chemical space around the molecular structure of 1 was explored by synthesizing and characterizing 220 derivatives and structurally related compounds. In addition to the synergistic transcriptional activation, selected compounds were evaluated for their effects on transcriptional activities of GATA4 and NKX2-5 individually as well as potential cytotoxicity. The structure-activity relationship (SAR) analysis revealed that the aromatic isoxazole substituent in the southern part regulates the inhibition of GATA4-NKX2-5 transcriptional synergy. Moreover, inhibition of GATA4 transcriptional activity correlated with the reduced cell viability. In summary, comprehensive SAR analysis accompanied by data analysis successfully identified potent and selective inhibitors of GATA4-NKX2-5 transcriptional synergy and revealed structural features important for it.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume62
Issue number17
Pages (from-to)8284-8310
Number of pages27
ISSN0022-2623
DOIs
Publication statusPublished - 12 Sep 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • DEFECTS
  • DISCOVERY
  • FIBROBLASTS
  • MUTATIONS
  • REQUIREMENT
  • SMALL MOLECULES
  • TRANSCRIPTION FACTORS
  • 317 Pharmacy
  • 116 Chemical sciences

Equipment

Viikki Metabolomics Unit - ViMU

Nina Sipari (Manager)

Facility/equipment: Equipment

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