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Therapeutic targeting K<jats:sub>V<\/jats:sub>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<jats:sub>V<\/jats:sub>1.3\u2010targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K<jats:sub>V<\/jats:sub>1.3 peptide and small\u2010molecule inhibitors, and strategies to improve the selectivity of active compounds toward K<jats:sub>V<\/jats:sub>1.3. Selectivity of dalatazide (ShK\u2010186), 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\u2010molecule inhibitors are critically evaluated for their lead\u2010like characteristics and potential for progression into clinical development. Some small\u2010molecule inhibitors with well\u2010defined structure\u2013activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K<jats:sub>V<\/jats:sub>1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K<jats:sub>V<\/jats:sub>1.3 modulators against this target in the future.<\/jats:p>","DOI":"10.1002\/med.21800","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T13:41:22Z","timestamp":1619876482000},"page":"2423-2473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Discovery of K<sub>V<\/sub>1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2982-309X","authenticated-orcid":false,"given":"\u0160pela","family":"Gubi\u010d","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise 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