GATA4-NKX2-5-IN-1 (3i-1000) is a small-molecule compound inhibiting GATA4 and NKX2-5 transcriptional synergy with IC50 of 3µM [1].
GATA4-NKX2-5-IN-1 inhibits hypertrophic growth. GATA4-NKX2-5-IN-1 (10µM, 48h) significantly inhibited the increase in the area of the myocytes in response to the mechanical stretching (48h) [1]. GATA4-NKX2-5-IN-1 (30µM), inhibited epidermal growth factor receptor kinase (EGFR) by 54% and vascular endothelial growth factor receptor 2 kinase/kinase insert domain receptor (VEGFR2/KDR) by 64% [1]. GATA4-NKX2-5-IN-1 inhibited cannabinoid receptor type 2 (CB2), parathyroid hormone 2 receptor (PTH2), and niacin receptor 1/G-protein-coupled receptor 109A (GPR109A) with mean percentage inhibition values of 91.8, 59.5, and 58.5, respectively [1]. GATA4-NKX2-5-IN-1 inhibits BNP transcription, and stretch-, endothelin-1- and phenylephrine-stimulated gene expression of ANP and BNP, as well as hypertrophic cell growth in cardiomyocytes while having no effect on GATA4 or NKX2-5 DNA binding or on the activity of protein kinases involved in the regulation of GATA4 phosphorylation [1,2]. GATA4-NKX2-5-IN-1 showed cardioprotective effects in vitro. It attenuated doxorubicin-induced increase in proBNP expression in hiPSC-CMs after a 4-day exposure. GATA4-NKX2-5-IN-1 (3 µM, 10 µM) attenuated doxorubicin-induced increase in caspase activation up to 14 days. however the long-term exposures (up to 21 days), revealed toxic effects of GATA4-NKX2-5-IN-1 in cardiomyocytes [3].
GATA4-NKX2-5-IN-1(30mg/kg/day i.p.) significantly improved left ventricular ejection fraction and fractional shortening, and attenuated myocardial structural changes in mice after myocardial infarction. GATA4-NKX2-5-IN-1 improved cardiac function in an experimental model of angiotensin II -mediated hypertension in rats. The concentration of GATA4-NKX2-5-IN-1 was highest at 0.5h and decreased to about half within 6h in vivo in rats (single dose i.p. 10mg/kg) [2].
References:
[1]. Va?lima?ki M J, To?lli M A, Kinnunen S M, et al. Discovery of small molecules targeting the synergy of cardiac transcription factors GATA4 and NKX2-5[J]. Journal of Medicinal Chemistry, 2017, 60(18): 7781-7798.
[2]. Kinnunen S M, TÖlli M, VÄlimÄki M J, et al. Cardiac actions of a small molecule inhibitor targeting GATA4-NKX2-5 interaction[J]. Scientific reports, 2018, 8(1): 1-14.
[3]. Karhu S T, Kinnunen S M, TÖlli M, et al. GATA4-targeted compound exhibits cardioprotective actions against doxorubicin-induced toxicity in vitro and in vivo: establishment of a chronic cardiotoxicity model using human iPSC-derived cardiomyocytes[J]. Archives of Toxicology, 2020, 94(6): 2113-2130.