GATA4-NKX2-5-IN-1
(Synonyms: 3i-1000) 目录号 : GC25450GATA4-NKX2-5-IN-1 (3i-1000) is a small-molecule compound inhibiting GATA4 and NKX2-5 transcriptional synergy with IC50 of 3 uM
Cas No.:544681-96-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) cells |
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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. |
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Reaction Conditions |
0-10 µM, 2-21 days |
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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]: | |
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Animal models |
male Sprague Dawley rats |
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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. |
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Dosage form |
15 mg/kg two times a day for 2 weeks, i.p. |
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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). |
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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. | |
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.
| Cas No. | 544681-96-1 | SDF | Download SDF |
| 别名 | 3i-1000 | ||
| 分子式 | C21H23N3O2 | 分子量 | 349.43 |
| 溶解度 | DMSO: 70 mg/mL (200.33 mM);Water: Insoluble;Ethanol: 9 mg/mL (25.76 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Targeting GATA4 for cardiac repair.
Sci Transl Med2021 Mar 31;13(587):eabg1168.PMID: 33790022DOI: 10.1002/iub.2150. Epub 2019 Aug 16.
Various strategies have been applied to replace the loss of cardiomyocytes in order to restore reduced cardiac function and prevent the progression of heart disease. Intensive research efforts in the field of cellular reprogramming and cell transplantation may eventually lead to efficient in vivo applications for the treatment of cardiac injuries, representing a novel treatment strategy for regenerative medicine. Modulation of cardiac transcription factor (TF) networks by chemical entities represents another viable option for therapeutic interventions. Comprehensive screening projects have revealed a number of molecular entities acting on molecular pathways highly critical for cellular lineage commitment and differentiation, including compounds targeting Wnt- and transforming growth factor beta (TGFβ)-signaling. Furthermore, previous studies have demonstrated that GATA4 and NKX2-5 are essential TFs in gene regulation of cardiac development and hypertrophy. For example, both of these TFs are required to fully activate mechanical stretch-responsive genes such as atrial natriuretic peptide and brain natriuretic peptide (BNP). We have previously reported that the compound 3i-1000 efficiently inhibited the synergy of the GATA4-NKX2-5 interaction. Cellular effects of 3i-1000 have been further characterized in a number of confirmatory in vitro bioassays, including rat cardiac myocytes and animal models of ischemic injury and angiotensin II-induced pressure overload, suggesting the potential for small molecule-induced cardioprotection.
Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4-NKX2-5 Interaction
Sci Rep.2018 Mar 15;8(1):4611.PMID: 29545582DOI: 10.1038/s41598-018-22830-8.
Transcription factors are fundamental regulators of gene transcription, and many diseases, such as heart diseases, are associated with deregulation of transcriptional networks. In the adult heart, zinc-finger transcription factor GATA4 is a critical regulator of cardiac repair and remodelling. Previous studies also suggest that NKX2-5 plays function role as a cofactor of GATA4. We have recently reported the identification of small molecules that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. Here, we examined the cardiac actions of a potent inhibitor (3i-1000) of GATA4-NKX2-5 interaction in experimental models of myocardial ischemic injury and pressure overload. In mice after myocardial infarction, 3i-1000 significantly improved left ventricular ejection fraction and fractional shortening, and attenuated myocardial structural changes. The compound also improved cardiac function in an experimental model of angiotensin II -mediated hypertension in rats. Furthermore, the up-regulation of cardiac gene expression induced by myocardial infarction and ischemia reduced with treatment of 3i-1000 or when micro- and nanoparticles loaded with 3i-1000 were injected intramyocardially or intravenously, respectively. The compound inhibited stretch- and phenylephrine-induced hypertrophic response in neonatal rat cardiomyocytes. These results indicate significant potential for small molecules targeting GATA4-NKX2-5 interaction to promote myocardial repair after myocardial infarction and other cardiac injuries.
GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line.
Stem Cell Res Ther.2021 Mar 18;12(1):190.PMID:33736688DOI: 10.1186/s13287-021-02259-z.
GATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.
Fabrication and Characterization of Drug-Loaded Conductive Poly(glycerol sebacate)/Nanoparticle-Based Composite Patch for Myocardial Infarction Applications
ACS Appl Mater Interfaces. 2020 Feb 12;12(6):6899-6909.PMID:31967771DOI: 10.1021/acsami.9b21066.
Heart tissue engineering is critical in the treatment of myocardial infarction, which may benefit from drug-releasing smart materials. In this study, we load a small molecule 3i-1000 in new biodegradable and conductive patches for application in infarcted myocardium. The composite patches consist of a biocompatible elastomer, poly(glycerol sebacate) (PGS), coupled with collagen type I, used to promote cell attachment. In addition, polypyrrole is incorporated because of its electrical conductivity and to induce cell signaling. Results from the in vitro experiments indicate a high density of cardiac myoblast cells attached on the patches, which stay viable for at least 1 month. The degradation of the patches does not show any cytotoxic effect, while 3i-1000 delivery induces cell proliferation. Conductive patches show high blood wettability and drug release, correlating with the rate of degradation of the PGS matrix. Together with the electrical conductivity and elongation characteristics, the developed biomaterial fits the mechanical, conductive, and biological demands required for cardiac treatment.