TRAM-34KCa3.1 blocker,potent and highly selective CAS# 289905-88-0 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 289905-88-0 | SDF | Download SDF |
PubChem ID | 656734 | Appearance | Powder |
Formula | C22H17ClN2 | M.Wt | 344.84 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Solubility | DMSO : 25 mg/mL (72.50 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) | ||
Chemical Name | 1-[(2-chlorophenyl)-diphenylmethyl]pyrazole | ||
SMILES | C1=CC=C(C=C1)C(C2=CC=CC=C2)(C3=CC=CC=C3Cl)N4C=CC=N4 | ||
Standard InChIKey | KBFUQFVFYYBHBT-UHFFFAOYSA-N | ||
Standard InChI | InChI=1S/C22H17ClN2/c23-21-15-8-7-14-20(21)22(25-17-9-16-24-25,18-10-3-1-4-11-18)19-12-5-2-6-13-19/h1-17H | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | TRAM-34 is a highly selective blocker of intermediate-conductance calcium-activated K+ channel (IKCa1) (Kd=20 nM). |
TRAM-34 Dilution Calculator
TRAM-34 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.8999 mL | 14.4995 mL | 28.999 mL | 57.9979 mL | 72.4974 mL |
5 mM | 0.58 mL | 2.8999 mL | 5.7998 mL | 11.5996 mL | 14.4995 mL |
10 mM | 0.29 mL | 1.4499 mL | 2.8999 mL | 5.7998 mL | 7.2497 mL |
50 mM | 0.058 mL | 0.29 mL | 0.58 mL | 1.16 mL | 1.4499 mL |
100 mM | 0.029 mL | 0.145 mL | 0.29 mL | 0.58 mL | 0.725 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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TRAM-34 is a highly selective inhibitor of KCa3.1 channel with IC50 value of 20 nM [1].
The Ca (2+)-binding protein calmodulin (CaM) confers Ca (2+) sensitivity to KCa3.1 of KCa3.1. On the basis of crystal structure obtained for the C-terminal region of the rat KCa2.2 channel (rSK2) with CaM that the binding of Ca (2+) to the CaM N-lobe results in CaM interlocking the C-terminal regions of two adjacent KCa3.1 subunits, leading to the formation of a dimeric structure. It is reported that many factors can increase KCa3.1, like balloon injury [2].
TRAM-34 is a KCa3.1 channel inhibitor and plays an important role in many diseases. When tested with human T cells, TRAM-34 treatment inhibited cells mobility and migration via blocking KCa3.1 channel [3]. In coronary smooth muscle cells isolated by laser capture microdissection, delivery of TRAM-34 via balloon catheter significantly blocked the KCa3.1 increase [4]. When tested with COS-7 cells, TRAM-34 inhibited KCa3.1 channel with Kd of 20 ± 3 nM and a Hill coefficient of 1.2 with 1 μM calcium in the pipette [1].
In male Wistar rat model of ischemic stroke, administration of TRAM-34 intraperitoneal (10 or 40 mg/kg, twice daily) for 7 days reduced infarction, neuronal death, microglia activation and neurological deficit via blocking KCa3.1 channel [5].
References:
[1].Wulff, H., et al., Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci U S A, 2000. 97(14): p. 8151-6.
[2].Kaushal, V., et al., The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J Neurosci, 2007. 27(1): p. 234-44.
[3].Chimote, A.A., et al., Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells. J Immunol, 2013. 191(12): p. 6273-80.
[4].Tharp, D.L., et al., Local delivery of the KCa3.1 blocker, TRAM-34, prevents acute angioplasty-induced coronary smooth muscle phenotypic modulation and limits stenosis. Arterioscler Thromb Vasc Biol, 2008. 28(6): p. 1084-9.
[5].Chen, Y.J., et al., The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke. J Cereb Blood Flow Metab, 2011. 31(12): p. 2363-74.
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Critical role of reactive oxygen species (ROS) for synergistic enhancement of apoptosis by vemurafenib and the potassium channel inhibitor TRAM-34 in melanoma cells.[Pubmed:28151482]
Cell Death Dis. 2017 Feb 2;8(2):e2594.
Inhibition of MAP kinase pathways by selective BRAF inhibitors, such as vemurafenib and dabrafenib, have evolved as key therapies of BRAF-mutated melanoma. However, tumor relapse and therapy resistance have remained as major problems, which may be addressed by combination with other pathway inhibitors. Here we identified the potassium channel inhibitor TRAM-34 as highly effective in combination with vemurafenib. Thus apoptosis was significantly enhanced and cell viability was decreased. The combination vemurafenib/TRAM-34 was also effective in vemurafenib-resistant cells, suggesting that acquired resistance may be overcome. Vemurafenib decreased ERK phosphorylation, suppressed antiapoptotic Mcl-1 and enhanced proapoptotic Puma and Bim. The combination resulted in enhancement of proapoptotic pathways as caspase-3 and loss of mitochondrial membrane potential. Indicating a special mechanism of vemurafenib-induced apoptosis, we found strong enhancement of intracellular ROS levels already at 1 h of treatment. The critical role of ROS was demonstrated by the antioxidant vitamin E (alpha-tocopherol), which decreased intracellular ROS as well as apoptosis. Also caspase activation and loss of mitochondrial membrane potential were suppressed, proving ROS as an upstream effect. Thus ROS represents an initial and independent apoptosis pathway in melanoma cells that is of particular importance for vemurafenib and its combination with TRAM-34.
KCa3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34.[Pubmed:27752766]
Pflugers Arch. 2016 Nov;468(11-12):1865-1875.
In the recent decades, ion channels became the focus of cancer biologists, as many channels are overexpressed in tumour tissue and functionally they are linked to abnormal cell behaviour with processes including apoptosis, chemo- and radioresistance, proliferation and migration. KCa3.1 is a Ca(2+)-activated K(+) channel that plays a central role in tumour progression in many cancer types. Therefore, the aim of the present study was to investigate KCa3.1 expression in pancreatic cancer cells and assess possible implications to disease progression. Using qPCR technique, we found abundant expression of KCa3.1 in pancreatic cancer cell lines. Patch clamp measurements on MiaPaCa-2 cells revealed a Ca(2+)-activated K(+) current that matched biophysical characteristics as described for KCa3.1. Moreover, the current was sensitive to the commonly used channel modulators TRAM-34, clotrimazole and DC-EBIO, and it was abolished following transient gene knockdown of KCa3.1. We utilized both pharmacology and RNAi to assess a possible role of the channel in tumour cell behaviour. We found that the channel supported MiaPaCa-2 cell proliferation. Using RNAi protocols, we also identified KCa3.1 as important entity in cell invasion. However, TRAM-34 had unexpected stimulatory effects on cell migration and invasion estimated in various assays. Moreover, TRAM-34 increased intracellular Ca(2+). In conclusion, we found prominent functional expression of KCa3.1 in pancreatic cancer cells. We provide evidence that the channel has a key role in cell proliferation and for the first time identify KCa3.1 as important entity in PDAC cell migration. We further reveal anomalous effects of TRAM-34.
[Effects of TRAM-34 on Proliferation and Invasion of Leukemia Cell Line HL-60].[Pubmed:28245384]
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2017 Feb;25(1):104-109.
OBJECTIVE: To investigate the effects of KCa3.1 channel inhibitor TRAM-34 on the proliferation and invasion of leukemia cell line HL-60. METHODS: HL-60 cells at logarithmic growth phase exposed to TRAM-34 at the final concentration of 25, 50, 75 and 100 nmol/L were used as experimental group. The HL-60 cells of control group was cultured in 10% fetal bovine serum-RPMI 1640. The proliferation inhibition rate of TRAM-34 on HL-60 cells was detected by adding MTT solution after 24, 48 and 72 h culture. The cell apoptotic rate and cell cycle distribution of HL-60 cells treated with TRAM-34 were evaluated by flow cytometry with Annexin V-FITC/propidium iodide(PI) double staining or PI single staining. The number of transmembrane cells was detected by Transwell at 24 and 48 h after treatment with TRAM-34. The effect of TRAM-34 on CDK6, P53 and MMP-2 mRNA level was detected by real-time quantitative PCR. RESULTS: Compared with the control group (0 nmol/L), the inhibition rate, apoptosis rate, G0/G1 phase cell proportion and P53 mRNA level all increased, but the percentages of cells in S phase, cell number penetrating the membrane and mRNA levels of CDK6 and MMP-2 in the TRAM-34-treated group decreased (P<0.05) except for 24 h proliferation rate of TRAM-34 at low concentration (25 nmol/L). The effect of TRAM-34 on the above indices was enhanced with the increase of concentration and prolongation of time, and the differences were statistically significant (P<0.05). CONCLUSION: TRAM-34 can inhibit the proliferation and invasion of HL-60 cells, and can induce cell apoptosis and G0/G1 arrest. The time and concentration of TRAM-34 have effect on the malignant behavior of HL-60 cells.
TRAM-34 inhibits nonselective cation channels.[Pubmed:17318643]
Pflugers Arch. 2007 Jul;454(4):559-63.
TRAM-34 has been demonstrated to inhibit intermediate-conductance Ca(2+)-activated K(+) channels in a wide variety of cell types, including immune cells. In the present study, we investigated effects of TRAM-34 on microglial cells stimulated with lysophosphatidylcholine (LPC). LPC-induced increases in the intracellular Ca(2+) concentration of microglial cells were effectively reduced in the presence of TRAM-34. At a concentration of 1 microM, TRAM-34 inhibited LPC-induced Ca(2+) signals by 60%. The TRAM-34-induced reduction of LPC-induced Ca(2+) increases cannot be related to the inhibition of Ca(2+)-activated K(+) channels. In contrast to TRAM-34, the Ca(2+)-activated K(+) channel inhibitor charybdotoxin did not affect LPC-induced increases in the intracellular Ca(2+) concentration of microglial cells. Patch clamp experiments revealed a direct inhibitory effect of TRAM-34 on nonselective cation channels. Half-maximal inhibition of LPC-induced nonselective cation currents was determined at 38 nM TRAM-34. These data indicate that TRAM-34 may cause additional effects on immune cells that are unrelated to the well-described inhibition of Ca(2+)-activated K(+) channels.
An intermediate-conductance Ca(2+)-activated K (+) channel mediates B lymphoma cell cycle progression induced by serum.[Pubmed:17429684]
Pflugers Arch. 2007 Sep;454(6):945-56.
We have previously reported that Kv1.3 channel is expressed in Daudi cells. However, the present study demonstrates that Daudi cell cycle progression is not affected by margatoxin, a Kv1.3 channel blocker, but can be suppressed by tetraethylammonium (TEA) and 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34), a selective blocker of intermediate-conductance Ca(2+)-activated K(+) (IK) channels. Our patch-clamp data indicate that Daudi cells express an IK channel because it has a unit conductance of about 30 pS, is voltage-independent, and can be activated by submicromolar Ca(2+) and blocked by TRAM-34. Fetal bovine serum (FBS) elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) and activated this IK channel. Conversely, Rituximab, a human-mouse chimeric monoclonal antibody of CD20, significantly decreased [Ca(2+)](i) and inhibited the channel. Furthermore, both FBS-induced IK channel expression and cell cycle progression were attenuated by the treatment with LY-294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. These data together suggest that a growth factor(s) in FBS triggers cell cycle progression by elevating both IK channel activity via CD20 and IK channel expression on the cell surface via PI3K. Thus, elevated IK channel activity and expression may account, in part, for Daudi cell malignant growth and proliferation.