hKVLQT1/MinK assays

Preclinical cardiac safety

hKVLQT1/MinK

hKVLQT1/MinK channel encoding for IKs current, plays an important role in the late phase cardiac action potential repolarisation. A pharmacological reduction of the IKs current may delay the repolarisation process and lead to a prolongation of the QT interval. The hKVLQT1/MinK channel is therefore considered as a specific target for cardiac safety assessment.

hKVLQT1/MinK assays & preclinical safety studies

The cardiac IKs channel (KCNQ1/KCNE1) is one of the main contributors to the repolarizing currents that regulate the ventricular action potential duration (APD) and thus the QT interval in the electrocardiogram. Mutations in cardiac KCNQ1/KCNE1 channels are the most common cause of congenital defects that cause long QT syndrome (LQTS). LQTS is a heart disorder that causes cardiac arrhythmias and 3000 to 4000 sudden deaths in children and young adults in the USA each year.

What is the added value of such a study?

  • Threshold concentration of KVLQT1/MinK blockade
  • Leading to the determination of the safety range versus efficacious concentration
  • You obtain your safety margin

Automated Patch Clamp

Technique

  • Human Embryonic Kidney HEK-293 cells
  • Experiment conducted at room temperature or at physiological temperature (35°C)
  • Up to 6 cumulative increasing concentrations of test compound or biologic.

Measured parameters

  • Amplitude of the tail current upon repolarization to –40mV (pA)
  • Amplitude of the base current at –80mV (pA)
  • Ion current amplitude measurement
  • Inhibition of hKvLQT1/MinK tail current amplitude (%)
  • IC50 value (at least 4 concentrations required)

Main advantages

  • High throughput screening
  • Cost effective
  • Fast process to delivery results
  • Perfect at earliest stages
  • Design protocol could be adapted

Manual Patch Clamp

Technique

  • Human Embryonic Kidney HEK-293 cells
  • Experiment conducted at room temperature or at physiological temperature (35°C)
  • Up to 5  increasing concentrations of test compound tested independently
  • At least 3 treated cells are recommended

Measured parameters

  • Amplitude of the tail current upon repolarization to –40mV (pA)
  • Amplitude of the base current at –80mV (pA)
  • Ion current amplitude measurement
  • Inhibition of hKvLQT1/MinK tail current amplitude (%)
  • IC50 value (at least 4 concentrations required)

Main advantages

  • Technically robust
  • Highly informative (more accurate IC50 value)
  • Strongly replicable
  • Design protocol could be adapted

Stimulation protocol

Typical effects of Chromanol on IKs current recorded from HEK-293 cells.

Ref­er­ence com­pounds

Reference CompoundsIC₅₀

XE-9911.5 µM

Chromanol 293B6.5 µM

Mefloquine0.7 µM

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