HERG-Lite® – hERG Channel Trafficking Assay
High Throughput, Non-Electrophysiological screening service for hERG risk
Identify compounds that produce hERG risk by trafficking inhibition. HERG-Lite® is a unique, rapid and cost-effective assay that monitors hERG expression at the cell surface. Trafficking-associated decreases in hERG activity occur hours after exposure to compound, but are as important to assessing risk as direct block. HERG-Lite® identifies hERG trafficking inhibitors by exposing wild-type (WT) hERG to drug overnight, and hERG channel blockers by measuring rescue of a trafficking-defective mutant hERG (SM) cell line.
Highlights:
- HERG-Lite® detects compounds, such as anti-cancer drugs like arsenic trioxide and geldanamycin derivations, that produce hERG risk by inhibiting protein trafficking from the endoplasmic reticulum.
- Also identifies compounds that block hERG directly.
- Fully validated against known hERG trafficking inhibitors, and tested on over 1,000 compounds
- Compounds are run at 3 concentrations in triplicate. Results provided 48 hours after study completion
Drug
|
Test Conc
|
Relative Surface Expression |
hERG Risk | |
hERG SM |
hERG WT |
|||
Arsenic Trioxide |
1 |
1.04 |
0.86 |
Yes |
10 |
0.87 |
0.35 |
||
Cisapride |
1 |
3.88 |
1.16 |
Yes |
10 |
5.05 |
1.19 |
||
Quinidine |
1 |
1.22 |
0.97 |
Yes |
10 |
1.80 |
1.11 |
||
Amiodarone |
1 |
1.51 |
0.99 |
Yes |
10 |
1.13 |
0.55 |
||
Thioridazine |
1 |
0.98 |
0.92 |
Yes |
10 |
0.99 |
0.50 |
||
Acetaminophen |
1 |
1.05 |
0.96 |
No |
10 |
1.06 |
0.96 |
||
Aspirin |
1 |
0.97 |
0.98 |
No |
10 |
1.08 |
0.99 |
||
Figure Legend:
HERG-Lite® results with known trafficking inhibitors and channel blockers. Highlighted values reflect significant changes from control surface expression. Decreased values for hERG expression in wild type (hERG-WT) cell line predict subunit trafficking inhibition. Elevated values for hERG expression in single mutant (hERG-SM) cell line due to chaperone effect from compound binding to the hERG channel in the ER.
References:
HERG-Lite®: a novel comprehensive high-throughput screen for drug-induced hERG risk
Wible BA, Hawryluk P, Ficker E, Kuryshev YA, Kirsch G, Brown AM (2005). J Pharmacol Toxicol Methods. 52(1):136-145Pentamidine-induced long QT syndrome and block of hERG trafficking Kuryshev YA, Ficker E, Wang L, Hawryluk P, Dennia AT, Wible BA, Brown AM, Kang J, Chen XL, Sawamura K, Reynolds W, Rampe D (2005). J Pharmacol Exp Ther. 312(1):316-323
Mechanisms of arsenic-induced prolongation of cardiac repolarization Ficker E, Kuryshev YA, Dennis AT, Obejero-Paz CA, Wang L, Wible BA, Brown AM (2004). Mol Pharmacol 66:33-44
Related Services:
CHAN-Lite™
Service assessing drug-induced trafficking channel inhibition of five critical cardiac channels (hERG, Kv1.5, Kv4.3, KvLQT1-minK, Kir2.1).