IQM-22110 as a selective K _V 4.3/KChIP3 modulator. Molecular determinants of the KChIP3 binding site

The goal of the present study was to discover novel KChIP ligands as research tools for modulating the K _V 4.3/KChIP channels. By employing a multidisciplinary approach, combining medicinal chemistry and electrophysiology studies, a novel K _V 4.3/KChIP modulator (IQM-22110) was successfully identified. IQM-22110 has emerged from the combination of our prior knowledge regarding the (phenylacetamido)benzoic acid moiety as an effective scaffold for KChIP3 ligands and a virtual screening of a focused chemical library. Guided by docking studies—which indicated that incorporating an additional aromatic ring could enhance binding affinity—IQM-22110 was selected for synthesis and identified as a potent KChIP3 ligand. Its electrophysiological effects on K _V 4.3/KChIP3 currents indicate that IQM-22110 binds to a high affinity site in K _V 4.3/KChIP3 channels that it is not present in K _V 4.3/KChIP2 or K _V 4.3. To the best of our knowledge, here we describe the first KChIP3 ligand that selectively modulates K _V 4.3/KChIP3 versus K _V 4.3/KChIP2 and K _V 4.3 alone channels. Given that KChIP2 is primarily expressed in heart, our findings might pave the way for the development of K _V 4.3/KChIP3 blockers with reduced cardiac side effects. Computational and site-directed mutagenesis studies allowed the identification of IQM-22110’s binding site on KChIP3. Knowledge gained from our structural and functional studies with this novel KChIP3 ligand could establish the basis for drug discovery programs fostering treatments for diseases in which K _V 4.3/KChIPs channels are involved.