The hERG-encoded K+ current, IKr is essential for repolarization of the cardiac action potential but also a source of
cardiotoxicity. Unintended hERG inhibition by diverse pharmaceutical agents can cause the acquired Long QT Syndrome
with ventricular arrhythmias and sudden cardiac death. As such, hERG inhibition represents one of the major reasons for adverse
drug events and drug withdrawal from the U.S. market. Indeed, the FDA requires testing of all new drugs for hERG-related pro-
arrhythmic potential. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC70 of
dofetilide, a well-characterized hERG blocker (PubChem AID1511). One compound (VU0405601), with the desired activity was
further characterized. In isolated, Langendorff-perfused rabbit hearts, dofetilide-induced arrhythmias were reduced following pre-
treatment with 5
M VU0405601. In heterologous hERG-HEK cells, dofetilide block of IKr develops gradually, with continuous
pulsing. VU0405601 protects hERG from dofetilide inhibition by increasing the IC50 of dofetilide from 38.7 nM in the absence to
76.3 nM in the presence of VU0405601. Investigation of structure activity relationships surrounding VU0405601 revealed three
key structural components: a 3-pyridyl amine moiety, an
-amidoether and a 2-substituted naphthyridine structure (substituted
with either halogen or methyl) that are important for protection from dofetilide inhibition. Development of a small molecule
that could be co-administered to decrease the risk of arrhythmias in response to hERG inhibitors would improve public health
and greatly facilitate the drug discovery process.
Sabina Kupershmidt completed her Ph.D. in Microbiology and Immunology in 1990 at Vanderbilt University. She remained at Vanderbilt and joined
Dr. Dan Roden?s lab in 1993 to apply molecular and biochemical methods to the study and arrhythmia mechanisms and received training in cardiac
electrophysiology which has been her field since then. In 2007, she was appointed to Research Associate Professor in Anesthesiology at Vanderbilt.
She has published more than 38 peer-reviewed articles and has served on numerous AHA and NIH grant-review committees. She has received
funding from the NIH and AHA.
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