Discovery of K 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges.

The K 1.3 voltage-gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting K 1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no K 1.3-targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K 1.3 peptide and small-molecule inhibitors, and strategies to improve the selectivity of active compounds toward K 1.3. Selectivity of dalatazide (ShK-186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small-molecule inhibitors are critically evaluated for their lead-like characteristics and potential for progression into clinical development. Some small-molecule inhibitors with well-defined structure-activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K 1.3 modulators against this target in the future.