The novel quinoline derivative SKA-346 as a K_Ca3.1 channel selective activator

The calcium-activated K_Ca3.1 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 K_Ca3.1 currents without affecting other channels. We synthesized five quinoline derivatives and used electrophysiology to screen them on K_Ca3.1 and a panel of 14 other ion channels. One quinoline derivative, SKA-346, activated K_Ca3.1 with an EC₅₀ of 1.9 μM and showed selectivity against the other channels. In silico 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 S₄₅A helix in the S4-S5 linker of the K_Ca3.1 channel. SKA-346 (30 mg kg⁻¹), tolerated by mice after intra-peritoneal administration, exhibited a peak plasma concentration of 6.29 μg mL⁻¹ (29.2 μM) at 15 min and a circulating half-life (t_1/2) of 2.8 h. SKA-346 could serve as a template for the development of more potent K_Ca3.1 activators to enhance T-cell cytotoxicity in cancer.