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Voltage-gated potassium channel K V 1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca 2+ homeostasis. Here, we present the structure-activity relationship, K V 1.3 inhibition, and immunosuppressive effects of new thiophene-based K V 1.3 inhibitors with nanomolar potency on K + current in T-lymphocytes and K V 1.3 inhibition on Ltk - cells. The new K V 1.3 inhibitor trans-18 inhibited K V 1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC 50 value of 26.1 nM and in mammalian Ltk - cells with an IC 50 value of 230 nM. The K V 1.3 inhibitor trans-18 also had nanomolar potency against K V 1.3 in Xenopus laevis oocytes (IC 50  = 136 nM). The novel thiophene-based K V 1.3 inhibitors impaired intracellular Ca 2+ signaling as well as T-cell activation, proliferation, and colony formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Expression of the voltage-gated potassium channel K V 10.1 (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 V 10.1 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 V 10.1 and hERG were investigated using whole-cell patch-clamp experiments. We obtained two new optimised K V 10.1 inhibitors, 17a and 18b , with improved nanomolar IC 50 values of 568 nM and 214 nM, respectively. Compound 17a exhibited better ratio between IC 50 values for hEAG1 and hERG than previously published diarylamine inhibitors. Compounds 17a and 18b moderately inhibited the growth of the K V 10.1-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 V 10.1 inhibitors remains the selectivity toward the hERG channel, which needs to be addressed with targeted drug design strategies in the future.

The voltage-gated potassium channel K V 1.3 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 V 1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency and selectivity of the new K V 1.3 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 V 1.3 inhibitor 44 in the series with an IC 50 value of 470 nM in oocytes and 950 nM in Ltk - cells. K V 1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14 , 37 , 43 , and 44 significantly inhibited Panc-1 proliferation.

Two decades of research have proven the relevance of ion channel expression for tumor progression in virtually every indication, and it has become clear that inhibition of specific ion channels will eventually become part of the oncology therapeutic arsenal. However, ion channels play relevant roles in all aspects of physiology, and specificity for the tumor tissue remains a challenge to avoid undesired effects. Eag1 (K V 10.1) is a voltage-gated potassium channel whose expression is very restricted in healthy tissues outside of the brain, while it is overexpressed in 70% of human tumors. Inhibition of Eag1 reduces tumor growth, but the search for potent inhibitors for tumor therapy suffers from the structural similarities with the cardiac HERG channel, a major off-target. Existing inhibitors show low specificity between the two channels, and screenings for Eag1 binders are prone to enrichment in compounds that also bind HERG. Rational drug design requires knowledge of the structure of the target and the understanding of structure-function relationships. Recent studies have shown subtle structural differences between Eag1 and HERG channels with profound functional impact. Thus, although both targets' structure is likely too similar to identify leads that exclusively bind to one of the channels, the structural information combined with the new knowledge of the functional relevance of particular residues or areas suggests the possibility of selective targeting of Eag1 in cancer therapies. Further development of selective Eag1 inhibitors can lead to first-in-class compounds for the treatment of different cancers., (© 2021 The Authors. Medicinal Research Reviews Published by Wiley Periodicals LLC.)

The K V 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 V 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 V 1.3-targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K V 1.3 peptide and small-molecule inhibitors, and strategies to improve the selectivity of active compounds toward K V 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 V 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K V 1.3 modulators against this target in the future., (© 2021 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)

(1) Background: The voltage-gated potassium channel K V 10.1 (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 V 10.1 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 IC 50 value of 3.70 µM against K V 10.1 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 V 10.1 inhibitor of the series with an IC 50 value of 740 nM, which was potent on the MCF-7 cell line expressing high K V 10.1 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 V 10.1 inhibitors. The main problem in the field of K V 10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods.

Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.

The voltage-gated potassium channel K v 1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which K v 1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the K v 1.3 channel. The screening resulted in two compounds inhibiting the K v 1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for K v 1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the K v 1.3 channel and three K v 1.3 mutants, designed to resemble the pore region of K v 1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the K v 1.3 channel, resulting in a 20-fold higher potency for TVS-12., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)