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Purity: ≥98%
PD-118057 (PD118057) is a novel and potent hERG (Human ether-a-go-go-related gene) channel enhancer. Human ether-a-go-go-related gene 1 (hERG1) K(+) channels mediate repolarization of cardiac action potentials.
| Targets |
hERG channel; Human ether-a-go-go-related gene channel
Human ether‑a‑go‑go‑related gene (hERG or KCNH2) potassium channel activator . [1] |
|---|---|
| ln Vitro |
PD-118057 (3 μM and 10 μM) specifically enhanced hERG currents and inhibited action potential duration in the ventricular myocardium of acutely isolated guinea pig cardiomyocytes [2-3]. With no change in the "hump" shape of the IKr current recorded by action potential clamp, PD-118057 (10 μM) reversed the current suppression caused by Dof and Mox and only marginally enhanced the peak value of the suppressed current [3].
PD‑118057 (3 μM) significantly enhanced both the maximum current amplitude and tail current amplitude of WT‑hERG channels expressed in HEK293 cells, but did not alter the gating and kinetic properties of the WT‑hERG channel, except for accelerating steady‑state inactivation. [1] For the WT/E637K‑hERG channel (co‑expression of wild‑type and dominant‑negative E637K mutant), PD‑118057 had no effect on current amplitude, gating, or kinetic properties. [1] Western blot analysis showed that PD‑118057 treatment (3 μM for 24‑48 h) did not rescue the defective protein trafficking of E637K‑hERG or WT/E637K‑hERG channels, as indicated by the absence of the mature 155 kDa glycosylated band. [1] |
| Enzyme Assay |
IN THIS STUDY, WE INVESTIGATED: (a) the effect of PD-118057 and thapsigargin on the current amplitudes of WT-hERG and WT/E637K-hERG channels; (b) the effect of PD-118057 and thapsigargin on the biophysical properties of WT-hERG and WT/E637K-hERG channels; (c) whether drug treatment can rescue channel processing and trafficking defects of the WT/E637K-hERG mutant.
Methods: The whole-cell Patch-clamp technique was used to assess the effect of PD-118057 and thapsigargin on the electrophysiological characteristics of the rapidly activating delayed rectifier K(+) current (Ikr) of the hERG protein channel. Western blot was done to investigate pharmacological rescue on hERG protein channel function. Results: In our study, PD-118057 was shown to significantly enhance both the maximum current amplitude and tail current amplitude, but did not alter the gating and kinetic properties of the WT-hERG channel, with the exception of accelerating steady-state inactivation. Additionally, thapsigargin shows a similar result as PD-118057 for the WT-hERG channel, but with the exception of attenuating steady-state inactivation. However, for the WT/E637K-hERG channel, PD-118057 had no effect on either the current or on the gating and kinetic properties. Furthermore, thapsigargin treatment did not alter the current or the gating and kinetic properties of the WT/E637K-hERG channel, with the exception of opening at more positive voltages. Conclusion: Our findings illustrate that neither PD-118057 nor thapsigargin play a role in correcting the dominant-negative effect of the E637K-hERG mutant[1]. |
| Cell Assay |
Cell Lines and Drug Exposure[1]
Human embryonic kidney 293 (HEK293) cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum in 5% CO2 incubator at 37°C. HEK293 cells were transiently transfected with 3.2 µg of WT-hERG and/or 3.2 µg of E637K-hERG plasmids using Lipofectamine™ 2000 according to the manufacturer’s instruction. 0.8 µg of pRK5-GFP plasmid was co-transfected to monitor transfection efficacy. Thapsigargin (1 mmol/L stock dissolved in DMSO), PD-118057 (5 mmol/L stock dissolved in DMSO) were added to the culture media for different time periods before analyzing. Final DMSO concentrations in medium was <0.1%.Incubating HEK293 cells expressing WT-hERG, WT/E637K-hERG or E637K-hERG overnight in 0.1% DMSO had no effect on IhERG or complex glycosylation. Whole‑cell patch‑clamp recordings were performed on HEK293 cells transiently transfected with WT‑hERG, E637K‑hERG, or WT/E637K‑hERG plasmids. Cells were treated with 3 μM PD‑118057 (dissolved in DMSO, final DMSO concentration <0.1%) for 48 h before recording. Currents were elicited by voltage‑clamp protocols, and data were analyzed for current amplitude, activation, inactivation, recovery from inactivation, and deactivation. [1] Western blot analysis was performed on HEK293 cells expressing hERG channels. Cells were solubilized in RIPA buffer with protease inhibitors, proteins were separated on 8% SDS‑PAGE, transferred to PVDF membranes, and probed with rabbit polyclonal anti‑HERG antibody followed by alkaline phosphatase‑conjugated secondary antibody. Protein bands were detected using BCIP/NBT substrate. [1] |
| References |
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| Additional Infomation |
Previous studies have shown that mouse portal vein myocytes express ether-a-go-go-related genes (ERGs) and exhibit unique currents when recorded under symmetric K+ conditions. This study aimed to characterize ERG channel currents induced by negative clamping potentials under conditions closer to physiological states to assess the potential functional impact of this conductance. Currents were recorded at a clamping potential of -60 mV using ruptured or perforated patch-clamp variants of the whole-cell patch-clamp technique. Three structurally different selective ERG channel blockers—E-4031, dofetilide, and peptidotoxin BeKM-1—significantly inhibited outward currents and eliminated inward currents with unique "hook-like" kinetics recorded during repolarization. At a negative potential induced by depolarization to +40 mV, the dofetilide-sensitive current exhibited voltage-dependent peak time and decay rate characteristic of ERG channels. The application of the novel ERG channel activator PD-118057 (1-10 μM) significantly enhanced the hook-inward current induced by membrane depolarization and hyperpolarized the resting membrane potential by about 20 mV recorded by current clamp and perforated patch clamp. In contrast, blocking the ERG channel with dofetilide (1 μM) depolarized the resting membrane potential by about 8 mV. These data are the first to record ERG channel currents in smooth muscle cells under quasi-physiological conditions, indicating that ERG channels are involved in maintaining the resting membrane potential of these cells. [2] PD-118057 is a small molecule activator of hERG channels that can enhance hERG currents without blocking the channels, making it a potential candidate for the treatment of long QT syndrome type 2 (LQT2). [1] This study suggests that PD-118057 may increase the current amplitude by directly binding to the channel and increasing its opening probability, rather than through an indirect mechanism. [1]
PD-118057 failed to rescue the dominant negative effects of the E637K-hERG mutant on channel function and transport, suggesting that its efficacy may depend on specific channel conformations or regions (e.g., pore-S6 loop). [1] |
| Molecular Formula |
C21H17CL2NO2
|
|---|---|
| Molecular Weight |
386.271183729172
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| Exact Mass |
385.064
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| Elemental Analysis |
C, 65.30; H, 4.44; Cl, 18.35; N, 3.63; O, 8.28
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| CAS # |
313674-97-4
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| PubChem CID |
9864959
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.353g/cm3
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| Boiling Point |
527ºC at 760 mmHg
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| Flash Point |
272.52ºC
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| Index of Refraction |
1.668
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| LogP |
6.293
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
453
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ZCQOSCDABPVAFB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H17Cl2NO2/c22-18-12-9-15(13-19(18)23)6-5-14-7-10-16(11-8-14)24-20-4-2-1-3-17(20)21(25)26/h1-4,7-13,24H,5-6H2,(H,25,26)
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| Chemical Name |
2-[4-[2-(3,4-Dichlorophenyl)ethyl]anilino]benzoic acid
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| Synonyms |
PD118057; PD-118057; PD-118057; 313674-97-4; 2-[[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]amino]benzoic acid; 2-[4-[2-(3,4-dichlorophenyl)ethyl]anilino]benzoic acid; 2-((4-(3,4-dichlorophenethyl)phenyl)amino)benzoic acid; 2-({4-[2-(3,4-DICHLOROPHENYL)ETHYL]PHENYL}AMINO)BENZOIC ACID; ZCQOSCDABPVAFB-UHFFFAOYSA-N; PD 118057
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~258.89 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5889 mL | 12.9443 mL | 25.8886 mL | |
| 5 mM | 0.5178 mL | 2.5889 mL | 5.1777 mL | |
| 10 mM | 0.2589 mL | 1.2944 mL | 2.5889 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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