Synthesis, identification and structure-activity relationship analysis of GATA4 and NKX2-5 protein-protein interaction modulators

Antti Mikael Jumppanen, Sini M. Kinnunen, Mika Juhani Välimäki, Virpi Talman, Samuli Auno, Tanja Bruun, Gustav Boije af Gennäs, Henri Guillaume Michel Xhaard, Ingo Bernhard Aumuller, Heikki Ruskoaho, Jari Yli-Kauhaluoma

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review


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.

TidskriftJournal of Medicinal Chemistry
Sidor (från-till)8284-8310
Antal sidor27
StatusPublicerad - 12 sep. 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad


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