Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2‑5

Transcription
factors
are pivotal regulators of gene transcription,
and many diseases are associated with the deregulation of transcriptional
networks. In the heart, the transcription factors GATA4 and NKX2-5
are required for cardiogenesis. GATA4 and NKX2-5 interact physically,
and the activation of GATA4, in cooperation with NKX2-5, is essential
for stretch-induced cardiomyocyte hypertrophy. Here, we report the
identification of four small molecule families that either inhibit
or enhance the GATA4–NKX2-5 transcriptional synergy. A fragment-based
screening, reporter gene assay, and pharmacophore search were utilized
for the small molecule screening, identification, and optimization.
The compounds modulated the hypertrophic agonist-induced cardiac gene
expression. The most potent hit compound, N-[4-(diethylamino)­phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide
(3, IC50 = 3 μM), exhibited no activity
on the protein kinases involved in the regulation of GATA4 phosphorylation.
The identified and chemically and biologically characterized active
compound, and its derivatives may provide a novel class of small molecules
for modulating heart regeneration.