Antibody-based Validation of CNS Ion Channel Drug Targets

Target validation and selection are critical early steps in the drug discovery process as they trigger substantial activity and investment to identify potential drug candidates. Antibodies play a crucial role in target selection as they provide powerful tools to explore the distribution and subcellular location of candidate molecules and can also be used to explore function. For studies of ion channel targets, antibodies are indispensable as they allow for direct exploration of the subunit composition of channel complexes in native tissues using biochemical and anatomical methods. This perspective summarizes the application of antibodies to target characterization and validation within the context of a CNS therapeutic discovery program targeting voltage-gated K + channels. We also discuss a strategy for the development, characterization, and validation of high-quality antibody reagents to support key activities in drug discovery. Target selection is perhaps the most critical step in early drug discovery. This seminal event — deciding which target to pursue, its level of " validation " for a specifi c medical condition and whether to pursue it with a small or large molecule, agonist or antagonist, etc. — triggers a number of downstream activities requiring substantial investments of time, personnel, and fi nancial resources. The processes and events leading up to ion channel target selection are complex and vary widely across the pharmaceutical/biotechnology industries and aca-demia. However, once an ion channel target has been selected, the approaches for its rigorous characterization are common, requiring a systematic, multidisciplinary effort spanning genetics, anatomy, biochemistry, cell biology, and electrophysiology. Although all candidate drug targets require detailed characterization in order to be pursued effectively, multisubunit ion channels are among the most challenging and, owing to the array of cell types, diversity of channel phenotypes and highly polarized neuronal architecture, CNS channels are particularly daunting. The aim of this Perspective is to describe some of the challenges to ion channel target Abbreviations used in this paper: BK ␣ , BK channel ␣ subunit; KChIP, Kv channel interacting protein; Kv, voltage-gated potassium. characterization and selection for drug discovery, based on experiences within CNS drug discovery programs focused on neuronal voltage-gated K + (Kv) channels. A cornerstone of these programs was the development of specifi c, extensively characterized antibody reagents that could be used to generate detailed information on the distribution, subcellular localization, and molecular composition of individual channel complexes, as a basis for target selection and to help identify potential therapeutic …