The study identified structural features, specifically an aromatic isoxazole substituent, crucial for the selective inhibition of GATA4-NKX2-5 transcriptional synergy.
These preclinical inhibitors should not yet inform practice; leaves open translation to cardiac disease models.
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.
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Jumppanen et al. (2019) studied this question.
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