BPS2026 – Discovery of a small molecular modulator of the cellular trafficking of the KCNQ1 potassium channel

Type 1 long QT syndrome (LQT1) increases the risk of cardiac arrythmia and sudden death and is caused by variations in the voltage-gated potassium channel KCNQ1. There are more than 250 known LQT1-associated variants in KCNQ1, and previous studies have found that these variants most commonly alter channel levels in the cell and/or result in reduced trafficking to the plasma membrane (mistrafficking). We tested whether small molecules can be discovered that rescue KCNQ1 from mistrafficking and/or that increase its expression levels to provide proof of concept support for such molecules as potential LQT1 therapeutics. A high-content image-based trafficking assay was used to screen for compounds that alter the cell surface levels, total levels, and/or trafficking of KCNQ1. We identified VU0494372, a small molecule that increases cell surface and total levels of wild type KCNQ1 as well as its cell surface trafficking efficiency. We characterized the impact of VU0494372 on three LQTS-associated KCNQ1 variants and found that it increased cell surface levels and trafficking efficiency for all three variants by ∼2-fold or more. Further study revealed that VU0494372 exhibits an EC50 of 10-15 μM, does not alter KCNQ1 transcription, degradation, or thermal stability, and appears to directly interact with KCNQ1 at or near the binding site of a known KCNQ1 modulator, ML277. Additionally, we found that 16-h treatment of cells with VU0494372 increased currents for wild type KCNQ1 and LQT1-associated variant V207M. This work demonstrates that pharmacological agents can be found that increase the expression and cell surface trafficking of human KCNQ1.