The novel quinoline derivative SKA-346 as a K3.1 channel selective activator.

The calcium-activated K3.1 channel plays a crucial role in T-cell immune response. Genetic manipulation of T-cells to upregulate the expression of K channels has been shown to boost T-cell cytotoxicity in cancer. Here, we aimed to identify and characterize an activator that would augment K3.1 currents without affecting other channels. We synthesized five quinoline derivatives and used electrophysiology to screen them on K3.1 and a panel of 14 other ion channels. One quinoline derivative, SKA-346, activated K3.1 with an EC of 1.9 μM and showed selectivity against the other channels. analysis using RosettaLigand and GLIDE demonstrated a well-converged pose of SKA-346 in a binding pocket at the interface between the calmodulin N-lobe and the SA helix in the S4-S5 linker of the K3.1 channel. SKA-346 (30 mg kg), tolerated by mice after intra-peritoneal administration, exhibited a peak plasma concentration of 6.29 μg mL (29.2 μM) at 15 min and a circulating half-life ( ) of 2.8 h. SKA-346 could serve as a template for the development of more potent K3.1 activators to enhance T-cell cytotoxicity in cancer.