Home>>Signaling Pathways>> TGF-β / Smad Signaling>> TGF-β Receptor>>A 83-01

A 83-01 Sale

(Synonyms: 3-(6-甲基-2-吡啶基)-N-苯基-4-(4-喹啉基)-1H-吡唑-1-硫代甲酰胺,A83-01;A-83-01) 目录号 : GC10166

A TGF-β type I receptor inhibitor

A 83-01 Chemical Structure

Cas No.:909910-43-6

规格 价格 库存 购买数量
1mg
¥280.00
现货
5mg
¥420.00
现货
10mg
¥679.00
现货
50mg
¥2,030.00
现货
100mg
¥3,150.00
现货

电话:400-920-5774 Email: sales@glpbio.cn

Customer Reviews

Based on customer reviews.

Sample solution is provided at 25 µL, 10mM.

产品文档

Quality Control & SDS

View current batch:

实验参考方法

Cell experiment [1]:

Cell lines

Mv1Lu and C2C12 cells

Preparation Method

Cells were pretreated for 1 h with 1uM small molecule inhibitors A 83-01 and then cultured with TGF-β.

Reaction Conditions

1uM A-83-01, 1 h

Applications

The effects of TGF-β inhibitors on cell proliferation were examined. A 83-01 efficiently prevented the growth-inhibitory effects of TGF-β, A-83-01 prevented inhibition of growth of Mv1Lu cells by TGF-β in a dose-dependent fashion. Treatment with 0.3 uM A 83-01 completely blocked the growth-inhibitory effect of TGF-β.

Animal experiment [2]:

Animal models

M109 cells were inoculated subcutaneously into CDF1 female mice (5 weeks old)

Preparation Method

When the tumor volume reached approximately 100-200 mm3, SL, F-SL, or free DXR was injected intravenously at 8 mg/kg, with or without intraperitoneal injection of 0.5 mg A 83-01/kg. The control group was injected intravenously with saline (0.2 mL/20 g body weight) with intraperitoneal injection of the vehicle (0.1 mL/20 g body weight).

Dosage form

0.5 mg A-83-01/kg,16day

Applications

The liposomal DXR injected group showed a strong antitumor effect in comparison with saline with or without A 83-01 and free DXR treated groups. A 83-01 alone did not show an antitumor effect. F-SL with A 83-01 showed a significantly stronger antitumor effect than F-SL alone on day 7 and days 13 and 16, SL alone on day 7 and days 10 and 13, or SL with A 83-01 on days 7 and 10.

References:

[1]. Tojo M, Hamashima Y, et,al. The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 2005 Nov;96(11):791-800. doi: 10.1111/j.1349-7006.2005.00103.x. PMID: 16271073.

[2]. Taniguchi Y, Kawano K, et,al. Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor. Cancer Sci. 2010 Oct;101(10):2207-13. doi: 10.1111/j.1349-7006.2010.01646.x. Epub 2010 Jul 1. PMID: 20608940.

产品描述

A 83-01 is a potent inhibitor of TGF-β type I receptor ALK5 kinase, type I nodal receptor ALK4 and type I nodal receptor ALK7, with IC50 s of 12 nM,45 nM and 7.5 nM against the transcription induced by ALK5, ALK4 and ALK7, respectively [1].

A 83-01 reduces the level of ALK-5-induced transcription in Mv1Lu cells, also blocks the ALK4-TD and ALK7-TD induced transcription R4-2 cells, and weakly suppresses that induced by constitutively active ALK-6, ALK-2, ALK-3, and ALK-1. A 83-01 (0.03-10 μM) potently prevents the growth-inhibitory effects of TGF-β, and completely inhibits the effect at 3 μM. A 83-01 (1-10 μM) inhibits TGF-β-induced Smad activation in HaCaT cells [1]. A 83-01 (1 μM) decreases cell motility, adhesion and invasion increased by TGF-β1 in HM-1 cells, but does not change cell proliferation [2]. A-83-01-treated retinal pigment epithelium (RPE) failed to differentiate after 7 passages (P7). Exogenous expression of MYCN and OTX2 in conjunction with A 83-01 restored P7-RPE differentiation to a status similar to minimally passaged RPE [5].

When co-administrated F-SL with A 83-01. Intraperitoneally injected A 83-01-induced alterations in the cancer-associated neovasculature were examined by magnetic resonance imaging (MRI) and histological analysis. The targeting efficacy of single intravenous injections of F-SL combined with A 83-01 was evaluated by measurement of the biodistribution and the antitumor effect in mice bearing murine lung carcinoma M109. A 83-01 temporarily changed the tumor vasculature around 3 h post injection. A 83-01 induced 1.7-fold higher drug accumulation of F-SL in the tumor than liposome alone at 24 h post injection. Moreover F-SL co-administrated with A 83-01 showed significantly greater antitumor activity than F-SL alone [3]. A 83-01 treatment significantly increased the number of Nkx2.5(+) cardiomyoblasts at baseline and after myocardial injury, resulting in an increase in newly formed cardiomyocytes [6]. Using transgenic Nkx2.5 enhancer-green fluorescent protein (GFP) reporter mice, and isolated cardiac progenitor cells (CPC). A 83-01 was found to induce proliferation mainly through increasing Birc5 expression in the MEK/ERK-dependent pathway [7]. Treatment of rat dermal fibroblast with A 83-01 inhibited transforming growth factor-β1 (TGF-β1)-dependent induction of α-SMA and collagen type I [4].

References:
[1]: Tojo M, Hamashima Y, et,al. The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 2005 Nov;96(11):791-800. doi: 10.1111/j.1349-7006.2005.00103.x. PMID: 16271073.
[2]: Yamamura S, Matsumura N, et,al. The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer. 2012 Jan 1;130(1):20-8. doi: 10.1002/ijc.25961. Epub 2011 Apr 18. PMID: 21503873.
[3]: Taniguchi Y, Kawano K, et,al. Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor. Cancer Sci. 2010 Oct;101(10):2207-13. doi: 10.1111/j.1349-7006.2010.01646.x. Epub 2010 Jul 1. PMID: 20608940.
[4]: Sun X, Kim YH, et,al. Topical application of ALK5 inhibitor A-83-01 reduces burn wound contraction in rats by suppressing myofibroblast population. Biosci Biotechnol Biochem. 2014;78(11):1805-12. doi: 10.1080/09168451.2014.932666. Epub 2014 Jul 10. PMID: 25351330.
[5]:Shih YH, Radeke MJ, et,al. Restoration of Mesenchymal RPE by Transcription Factor-Mediated Reprogramming. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):430-441. doi: 10.1167/iovs.16-20018. PMID: 28118667.
[6]: Chen WP, Liu YH, et,al. Pharmacological inhibition of TGFβ receptor improves Nkx2.5 cardiomyoblast-mediated regeneration. Cardiovasc Res. 2015 Jan 1;105(1):44-54. doi: 10.1093/cvr/cvu229. Epub 2014 Oct 31. PMID: 25362681; PMCID: PMC4342671.
[7]: Ho YS, Tsai WH,et,al. Cardioprotective Actions of TGFβRI Inhibition Through Stimulating Autocrine/Paracrine of Survivin and Inhibiting Wnt in Cardiac Progenitors. Stem Cells. 2016 Feb;34(2):445-55. doi: 10.1002/stem.2216. Epub 2015 Oct 10. PMID: 26418219.

A 83-01 是 TGF-β I 型受体 ALK5 激酶、I 型淋巴结受体 ALK4 和 I 型淋巴结受体 ALK7 的有效抑制剂,IC50 s 分别为 12 nM、45 nM和 7.5 nM 分别抑制 ALK5、ALK4 和 ALK7 诱导的转录[1]

A 83-01 降低 Mv1Lu 细胞中 ALK-5 诱导的转录水平,还阻断 ALK4-TD 和 ALK7-TD 诱导的转录 R4-2 细胞,并弱抑制由组成型活性 ALK-6 诱导的转录, ALK-2、ALK-3 和 ALK-1。 A 83-01 (0.03-10 μM) 有效阻止 TGF-β 的生长抑制作用,并在 3 μM 时完全抑制该作用。 A 83-01 (1-10 μM) 抑制 HaCaT 细胞中 TGF-β 诱导的 Smad 激活 [1]。 A 83-01 (1 μM) 降低 HM-1 细胞中 TGF-β1 增加的细胞运动性、粘附和侵袭,但不改变细胞增殖[2]。 A-83-01 处理的视网膜色素上皮细胞 (RPE) 在 7 代后无法分化 (P7)。 MYCN 和 OTX2 的外源表达与 A 83-01 一起将 P7-RPE 分化恢复到类似于最小传代 RPE 的状态[5]

当 F-SL 与 A 83-01 共同给药时。通过磁共振成像 (MRI) 和组织学分析检查腹膜内注射 A 83-01 诱导的癌症相关新生血管的改变。单次静脉内注射 F-SL 联合 A 83-01 的靶向功效通过测量生物分布和荷载肺癌 M109 小鼠的抗肿瘤作用来评估。 83-01 在注射后 3 小时左右暂时改变了肿瘤脉管系统。在注射后 24 小时,83-01 诱导的 F-SL 在肿瘤中的药物积累比单独的脂质体高 1.7 倍。此外,F-SL 与 A 83-01 联合给药显示出比单独使用 F-SL 显着更高的抗肿瘤活性[3]。 83-01 治疗显着增加了基线和心肌损伤后 Nkx2.5(+) 心肌细胞的数量,导致新形成的心肌细胞增加[6]。使用转基因 Nkx2.5 增强子-绿色荧光蛋白 (GFP) 报告小鼠和分离的心脏祖细胞 (CPC)。发现 A 83-01 主要通过增加 MEK/ERK 依赖通路中 Birc5 的表达来诱导增殖[7]。 A 83-01 处理大鼠真皮成纤维细胞可抑制转化生长因子-β1 (TGF-β1) 依赖的 α-SMA 和 I 型胶原的诱导[4]

Chemical Properties

Cas No. 909910-43-6 SDF
别名 3-(6-甲基-2-吡啶基)-N-苯基-4-(4-喹啉基)-1H-吡唑-1-硫代甲酰胺,A83-01;A-83-01
化学名 3-(6-methylpyridin-2-yl)-N-phenyl-4-quinolin-4-ylpyrazole-1-carbothioamide
Canonical SMILES CC1=CC=CC(=N1)C2=NN(C=C2C3=CC=NC4=CC=CC=C34)C(=S)NC5=CC=CC=C5
分子式 C25H19N5S 分子量 421.52
溶解度 100 mg/mL in DMSO (ultrasonic and warming and heat to 45°C), ≥ 9.82 mg/mL in EtOH with ultrasonic and warming 储存条件 -20°C, protect from light, stored under nitrogen,unstable in solution, ready to use.
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。
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。

溶解性数据

制备储备液
1 mg 5 mg 10 mg
1 mM 2.3724 mL 11.8618 mL 23.7237 mL
5 mM 0.4745 mL 2.3724 mL 4.7447 mL
10 mM 0.2372 mL 1.1862 mL 2.3724 mL
  • 摩尔浓度计算器

  • 稀释计算器

  • 分子量计算器

质量
=
浓度
x
体积
x
分子量
 
 
 
*在配置溶液时,请务必参考产品标签上、MSDS / COA(可在Glpbio的产品页面获得)批次特异的分子量使用本工具。

计算

动物体内配方计算器 (澄清溶液)

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
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

Research Update

Conversion of Terminally Committed Hepatocytes to Culturable Bipotent Progenitor Cells with Regenerative Capacity

Cell Stem Cell2017 Jan 5;20(1):41-55.PMID: 27840021DOI: 10.1016/j.stem.2016.10.007

A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and whether such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules, Y-27632, A-83-01, and CHIR99021, can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Thus, our study advances the goals of liver regenerative medicine.

The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta

Cancer Sci2005 Nov;96(11):791-800.PMID: 16271073DOI: 10.1111/j.1349-7006.2005.00103.x

Transforming growth factor (TGF)-beta signaling facilitates tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-beta signaling may thus be a novel strategy for the treatment of patients with such cancer. In this study, we synthesized and characterized a small molecule inhibitor, A-83-01, which is structurally similar to previously reported ALK-5 inhibitors developed by Sawyer et al. (2003) and blocks signaling of type I serine/threonine kinase receptors for cytokines of the TGF-beta superfamily (known as activin receptor-like kinases; ALKs). Using a TGF-beta-responsive reporter construct in mammalian cells, we found that A-83-01 inhibited the transcriptional activity induced by TGF-beta type I receptor ALK-5 and that by activin type IB receptor ALK-4 and nodal type I receptor ALK-7, the kinase domains of which are structurally highly related to those of ALK-5. A-83-01 was found to be more potent in the inhibition of ALK5 than a previously described ALK-5 inhibitor, SB-431542, and also to prevent phosphorylation of Smad2/3 and the growth inhibition induced by TGF-beta. In contrast, A-83-01 had little or no effect on bone morphogenetic protein type I receptors, p38 mitogen-activated protein kinase, or extracellular regulated kinase. Consistent with these findings, A-83-01 inhibited the epithelial-to-mesenchymal transition induced by TGF-beta, suggesting that A-83-01 and related molecules may be useful for preventing the progression of advanced cancers.

Topical application of ALK5 inhibitor A-83-01 reduces burn wound contraction in rats by suppressing myofibroblast population

Biosci Biotechnol Biochem2014;78(11):1805-12.PMID: 25351330DOI: 10.1080/09168451.2014.932666

Burn scar contracture that follows the healing of deep dermal burns causes severe deformation and functional impairment. However, its current therapeutic interventions are limited with unsatisfactory outcomes. When we treated deep second-degree burns in rat skin with activin-like kinase 5 (ALK5) inhibitor A-83-01, it reduced wound contraction and enhanced the area of re-epithelialization so that the overall time for wound closing was not altered. In addition, it reduced myofibroblast population in the dermis of burn scar with a diminished deposition of its biomarker proteins such as α-SMA and collagen. Treatment of rat dermal fibroblast with A-83-01 inhibited transforming growth factor-β1 (TGF-β1)-dependent induction of α-SMA and collagen type I. Taken together, these results suggest that topical application of ALK5 inhibitor A-83-01 could be effective in preventing the contraction of burn wound without delaying the wound closure by virtue of its inhibitory activity against the TGF-β-induced increase of myofibroblast population.

Restoration of Mesenchymal RPE by Transcription Factor-Mediated Reprogramming

Invest Ophthalmol Vis Sci2017 Jan 1;58(1):430-441.PMID: 28118667DOI: 10.1167/iovs.16-20018

Purpose: Transforming growth factor β-mediated epithelial-to-mesenchymal transition (EMT) is a major component of the wound healing response and a negative determinant of retinal pigment epithelium (RPE) differentiation. We have shown previously that inhibition of TGFβ signaling restored the capacity of mesenchymal RPE to differentiate; however, the potential lessens with extensive passaging. We investigated TGFβ-independent mechanisms that regulate RPE differentiation following repetitive passaging.
Methods: Retinal pigment epithelium-EMT was induced by repetitive passaging of fetal RPE at subconfluence. Suppression of EMT was achieved by the addition of A-83-01, a TGFβ receptor kinase inhibitor. Transcriptomic analysis was used to identify potential TGFβ independent processes that prevent differentiation after extensive passage. Downregulated transcription factors were identified and transduced into highly passaged RPE to restore cell differentiation. Restoration was evaluated according to morphology, expression of RPE/mesenchymal markers, transcriptomic analysis, cell doubling time, and senescence-associated β-galactosidase (SA-β-gal) activity.
Results: A-83-01-treated RPE failed to differentiate after 7 passages (P7). This failure was concomitant with downregulation of RPE genes, misregulation of cell cycle genes, a decline in proliferative potential, and cell senescence. Exogenous expression of MYCN and OTX2 in conjunction with A-83-01 restored P7-RPE differentiation to a status similar to minimally passaged RPE. Moreover, the treatment allowed cells to maintain their differentiation capacity after extended passaging.
Conclusions: Retinal pigment epithelium subjected to chronic wound stimulus undergoes TGFβ-mediated EMT, loss of expression of signature RPE genes, and senescence. Targeting these aspects with a TGFβ receptor kinase inhibitor, a RPE transcription factor, and a cell cycle regulator restores the capacity of highly passaged RPE cells to regenerate and differentiate.

Chemical conversion of aged hepatocytes into bipotent liver progenitor cells

Hepatol Res2021 Mar;51(3):323-335.PMID: 33378128DOI: 10.1111/hepr.13609

Aim: In the aging society, understanding the influence of hepatocyte age on hepatocyte donation may inform efforts to expand alternative cell sources to mitigate liver donor shortage. A combination of the molecules Y27632, A-83-01, and CHIR99021 has been used to reprogram rodent young hepatocytes into chemically induced liver progenitor (CLiP) cells; however, whether it could also reprogram aged hepatocytes has not yet been elucidated.
Methods: Primary hepatocytes were isolated from aged and young donor rats, respectively. Hepatic histological changes were evaluated. Differences in gene expression in hepatocytes were identified. The in vitro reprogramming plasticity of hepatocytes as evidenced by CLiP conversion and the hepatocyte and cholangiocyte maturation capacity of reprogrammed CLIPs were analyzed. The effect of hepatocyte growth factor (HGF) on cell propagation was also investigated.
Results: The histological findings revealed ongoing liver damage with inflammation, fibrosis, senescence, and ductular reaction in aged livers. Microarray analysis showed altered gene expression profiles in hepatocytes from aged donors, especially with regard to metabolic pathways. Aged hepatocytes could be converted into CLiPs (Aged-CLiPs) expressing progenitor cell markers, but with a relatively low proliferative rate compared with young hepatocytes. Aged-CLiPs possessed both hepatocyte and cholangiocyte maturation capacity. HGF facilitated CLiP conversion in aged hepatocytes, which was partly related to the activation of Erk1 and Akt1 signaling.
Conclusions: Aged rat hepatocytes have retained reprogramming plasticity as evidenced by CLiP conversion in culture. HGF promoted proliferation and CLiP conversion in aged hepatocytes. Hepatocytes from aged donors may be used as an alternative cell source to mitigate donor shortage.