The K_V1.3 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_V1.3 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_V1.3‐targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K_V1.3 peptide and small‐molecule inhibitors, and strategies to improve the selectivity of active compounds toward K_V1.3. 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_V1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K_V1.3 modulators against this target in the future.

(1) Background: The voltage-gated potassium channel K_V10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of K_V10.1 inhibitors. Whole-cell patch clamp experiments were used to investigate potency, selectivity, kinetics and mode of inhibition. Anticancer activity was determined using 2D and 3D cell-based models. (3) Results: The virtual screening hit compound ZVS-08 discovered by 3D pharmacophore modelling exhibited an IC₅₀ value of 3.70 µM against K_V10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent K_V10.1 inhibitor of the series with an IC₅₀ value of 740 nM, which was potent on the MCF-7 cell line expressing high K_V10.1 levels and low hERG levels, induced significant apoptosis in tumour spheroids of Colo-357 cells and was not mutagenic. (4) Conclusions: Computational ligand-based drug design methods can be successful in the discovery of new potent K_V10.1 inhibitors. The main problem in the field of K_V10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods.

The voltage-gated potassium channel K_V1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of K_V1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency and selectivity of the new K_V1.3 inhibitors were investigated using whole-cell patch- and voltage-clamp experiments. 2D and 3D cell models were used to determine antiproliferative activity. Structural optimization resulted in the most potent and selective K_V1.3 inhibitor 44 in the series with an IC₅₀ value of 470 nM in oocytes and 950 nM in Ltk⁻ cells. K_V1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation.

Expression of the voltage-gated potassium channel K_V10.1 (Eag1) has been detected in over 70% of human cancers, making the channel a promising new target for new anticancer drug discovery. A new structural class of K_V10.1 inhibitors was prepared by structural optimisation and exploration of the structure–activity relationship of the previously published hit compound ZVS-08 (1) and its optimised analogue 2. The potency and selectivity of the new inhibitors between K_V10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K_V10.1 inhibitors, 17a and 18b, with improved nanomolar IC₅₀ values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC₅₀ values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the K_V10.1-expressing cell line MCF-7 in two independent assays. In addition, 17a and 18b also inhibited the growth of hERG-expressing Panc-1 cells with higher potency compared with MCF-7 cells. The main obstacle for newly developed diarylamine K_V10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future.

In vitro models of the human nasal cavity are crucial for understanding the deposition dynamics of nasally administered drugs. Three-dimensional (3D) printing offers a powerful method for creating patient-specific, anatomically precise models for such experimental purposes. Background/Objectives: This study details the complete workflow for the development, design, and fabrication of a sectioned nasal cavity model intended for droplet deposition analysis of nasal sprays. Methods: A digital nasal cavity model was derived from medical imaging data and optimized for computer-aided design (CAD) operations. It was segmented into five therapeutically relevant regions: nasal vestibule, olfactory area, middle and upper turbinates, lower turbinate, and nasopharynx. Sections were 3D-printed in polypropylene for chemical compatibility, and a carbon fiber-reinforced fixation frame ensured precise alignment and airtight assembly. Results: Functional validation confirmed the model’s functional relevance through comparative deposition studies using automated actuation and high-performance liquid chromatography (HPLC) based regional quantification. Two devices with distinct spray characteristics (characterized separately by laser diffraction, plume geometry, and spray pattern imaging) were tested under varied administration conditions. The study demonstrated the model’s ability to discriminate between products, establishing a solid foundation for future investigations incorporating additional variables. Conclusions: Overall, the developed methodology provides a cost-effective and replicable platform for producing anatomically accurate, sectioned nasal cavity models. The newly developed in vitro system is well suited for detailed, region-specific analysis of nasal spray deposition, offering a valuable tool for pharmaceutical research and development.

The voltage-gated potassium channel KV1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of KV1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency, and selectivity of the new KV1.3 inhibitors were investigated using whole-cell patch- and voltage-clamp experiments. 2D and 3D cell models were used to determine antiproliferative activity. Structural optimization resulted in the most potent and selective KV1.3 inhibitor 44 in the series with an IC50 value of 470 nM in oocytes and 950 nM in Ltk cells. Kv1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation.