Identification of a new selective ligand for targeting neuronal K_V4.3/KChIP3 over cardiac K_V4.3/KChIP2 channels

The present study aimed to discover novel KChIP ligands as pharmacological tools for modulating the K_V4.3/KChIP channels. A multidisciplinary approach, combining medicinal chemistry and electrophysiology studies, led to the successfully identification of a novel K_V4.3/KChIP modulator (IQM-22110). Its design was guided by the previous knowledge of the (phenylacetamido)benzoic acid moiety as suitable scaffold, along with virtual screening of a focused chemical library that suggested improved KChIP3 binding upon incorporation of an additional aromatic ring. IQM-22110 was selected for synthesis and identified as a potent KChIP3 ligand. Its electrophysiological effects on K_V4.3/KChIP3 currents indicate that IQM-22110 binds to a high affinity site in K_V4.3/KChIP3 channels that it is not present in K_V4.3/KChIP2 or K_V4.3. To the best of our knowledge, here we describe the first KChIP3 ligand that selectively modulates K_V4.3/KChIP3 versus K_V4.3/KChIP2 and K_V4.3 channels at nanomolar concentration. Since KChIP2 is predominantly expressed in cardiac tissue, this selectivity may enable the development of K_V4.3/KChIP3-targeted therapeutics with reduced risk of cardiac side effects. Computational and site-directed mutagenesis studies allowed the identification of IQM-22110's binding site on KChIP3. Knowledge gained from structural and functional studies with this novel KChIP3 ligand could establish the basis for drug discovery programs fostering treatments for diseases in which K_V4.3/KChIPs channels are involved.