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GATA4-NKX2-5-IN-1 (Synonyms: 3i-1000)

Katalog-Nr.GC25450

GATA4-NKX2-5-IN-1 (3i-1000) is a small-molecule compound inhibiting GATA4 and NKX2-5 transcriptional synergy with IC50 of 3 uM

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GATA4-NKX2-5-IN-1 Chemische Struktur

Cas No.: 544681-96-1

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) cells

Preparation Method

The cells were exposed to doxorubicin and/or GATA4-NKX2-5-IN-1 for 2-21 days and cell viability was quantified with MTT assay. MTT was added to the cells at a final concentration of 0.5 mg/ml followed by 2 h incubation in cell culture conditions.

Reaction Conditions

0-10 µM, 2-21 days

Applications

In the MTT assay, GATA4-NKX2-5-IN-1 alone at 10 µM concentration reduced hiPSC-CM viability 34%, 50% and 65% after 7, 14 and 21 days of exposure, respectively. At the concentration of 3 µM, the decrease was only 16% even after 21-day exposure.

Animal experiment [2]:

Animal models

male Sprague Dawley rats

Preparation Method

Doxorubicin was administered i.p. to 7 weeks old male Sprague Dawley rats with average weight 216 g (range 189-245 g) at the dose of 1 mg/kg/day for 10 days. Control animals received an equivalent volume of saline. The compound GATA4-NKX2-5-IN-1 was administered i.p. at the dose of 15 mg/kg two times a day for 2 weeks from week 7 to week 9. It was diluted to DMSO and administered to animals as 1:1 dilution in corn oil, control animals receiving DMSO with corn oil in equivalent volume.

Dosage form

15 mg/kg two times a day for 2 weeks, i.p.

Applications

treatment with compound GATA4-NKX2-5-IN-1 significantly inhibited doxorubicin-induced cardiotoxicity by restoring the left ventricular ejection fraction (EF) and fractional shortening (FS).

References:

[1]: 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.

Background

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.

Chemical Properties

Cas No. 544681-96-1 SDF Download SDF
Überlieferungen 3i-1000
Formula C21H23N3O2 M.Wt 349.43
Löslichkeit DMSO: 70 mg/mL (200.33 mM);Water: Insoluble;Ethanol: 9 mg/mL (25.76 mM) Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

Prepare stock solution
1 mg 5 mg 10 mg
1 mM 2.8618 mL 14.309 mL 28.618 mL
5 mM 0.5724 mL 2.8618 mL 5.7236 mL
10 mM 0.2862 mL 1.4309 mL 2.8618 mL
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