Ion channels find a pathway for therapeutic success

Abstract

Drug discovery and development are complex processes that require long-term commitments to bring such efforts to fruition. Traditionally, there is low probability of success in being able to take new pharmacological agents all of the way through regulatory approval for use in man. There are multiple reasons that account for high failure rates of new investigational drugs, such as the manifestation of safety issues during development or lack of efficacy in clinical trials. Because costs of drug development have significantly escalated, partially as a consequence of stricter regulatory guidelines, it is important initially to identify the highest-quality small-molecule chemical drug leads for prosecution by medicinal chemistry, which fulfill the strictest criteria of potency and selectivity against the therapeutic target of interest. Optimization of such leads would eventually allow interrogation of the target in appropriate experimental medicine protocols to achieve early proof-of-concept in the clinic, which should increase probability of success upon further clinical investigation (1). It is remarkable that although ∼15% of currently used drugs target ion channels (2), this family of proteins remains largely unexplored for therapy, despite their significant contribution to a wide variety of physiological processes. Most approved ion channel drugs, such as Ca2+ channel blockers, sulfonylureas, antiarrhythmics, antiepileptics, and local anesthetics, were discovered and optimized using animal models of disease; it was only later that their mechanism of action was shown to be at the level of ion channel proteins (3). Despite the large number of academic and pharmaceutical groups working in this area, and significant progress made in understanding ion channel structure and function, molecular-based ion channel drug discovery research has advanced at a much slower pace than would have been anticipated after cloning of the human genome and identification of all of the ion channel families. Major reasons for the paucity of new drugs specifically targeting ion channels are a consequence of few satisfactory pharmacological tools targeting these proteins and incomplete understanding of precise roles of given ion channels in complex biological systems. To break through these barriers, there needs to be a facile way to identify new selective ion channel modulators with well-defined mechanisms of action that can be used to probe the physiological role of these proteins in native systems, and perhaps even to provide medicinal chemistry leads for new therapeutic agents. In PNAS, the article by Su et al. (4) describes one new elegant approach by which to accomplish these goals.