Targeting the Mitochondrial Potassium Channel Kv1.3 to Kill Cancer Cells: Drugs, Strategies, and New Perspectives

Prosdocimi, Elena; Checchetto, Vanessa; Leanza, Luigi

doi:10.1177/2472555219864894

Cited by 16 publications

(23 citation statements)

References 117 publications

(133 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although several K + channels reside in the inner mitochondrial membrane, K V 1.3 appears to be partly responsible for the basal K + conductance in mitochondria 56 . As the orientation and electrophysiological properties of K V 1.3 in mitochondria are the same as at the plasma membrane, both forms of the channel are likely the product of the same gene 35 …”

Section: Physiological and Pathological Functions Of Kv13mentioning

confidence: 99%

“…Psora‐4 ( 9b ), PAP‐1 ( 9c ), and clofazimine ( 10 ) inhibited mitochondrial K V 1.3 currents and induced apoptosis of different human and mouse cancer cell lines 35,47,184,185 . In K V 1.3 expressing mouse CTLL‐2 cells, these compounds invoked classical apoptosis pathways, with mitochondrial depolarization, elevated ROS production, cytochrome c release, and caspase‐3, caspase‐9, and poly(ADP‐ribose) polymerase cleavage.…”

Section: Drug Discovery Approaches For Designing New Kv13 Small‐molecule Inhibitorsmentioning

confidence: 99%

“…On the other hand, apoptosis does not occur in normal cells with upregulated K V 1.3 expression and in cancer cells with downregulated K V 1.3 expression. Some compounds have already been tested in vitro, ex vivo, and in vivo, which demonstrated that they could selectively kill cancer cells while sparing healthy cells 3,35,37,60 …”

Section: Specifically Targeting Mitochondrial Channels With Kv13 Ion Channel Modulatorsmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Gubič

Hendrickx

Sterle

et al. 2021

Medicinal Research Reviews

View full text Add to dashboard Cite

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.

show abstract

Section: Physiological and Pathological Functions Of Kv13mentioning

confidence: 99%

Section: Drug Discovery Approaches For Designing New Kv13 Small‐molecule Inhibitorsmentioning

confidence: 99%

Section: Specifically Targeting Mitochondrial Channels With Kv13 Ion Channel Modulatorsmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Gubič

Hendrickx

Sterle

et al. 2021

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…MitoKv1.3 biophysical features have been investigated principally studying the pharmacological features of Kv1.3 channels using the known inhibitors. Kv1.3 blockers can be divided in two categories: I) PM non-permeable, such as TEA, 4-AP, benzamide, Margatoxin (MgTx), Charybdotoxin (ChTx) and Stichodactyla Toxin (ShK); II) PM-permeable, like psoralens and their derivatives (5-(4-phenylobutoxy) psoralen (Psora-4), 5-(4-phenoxybutoxy) psoralen (PAP-1) and its derivatives) and the rhinophenazine clofazimine (N,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5Hphenazine-2-amine), already used for autoimmune disorders [30,31]. Only the second class are able to cross the PM and to block the mitoKv1.3 channels.…”

Section: Mitokv13 Featuresmentioning

confidence: 99%

Mitochondrial Kv1.3: a New Target in Cancer Biology?

2019

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…For both of these directions selective and effective inhibitors of K V 1.3 are desirable. Novel ligands and their derivatives are considered as promising molecular instruments in K V 1.3 research and are exploited as templates in drug design ( Wulff and Zhorov, 2008 ; Chandy and Norton, 2017 ; Prosdocimi et al, 2019 ). Active compounds affecting K V 1.3 can be obtained from different natural sources, such as plant extracts and animal venoms ( King, 2011 ; Norton and Chandy, 2017 ), as well as synthesized de novo ( Schmitz et al, 2005 ; Hendrickx et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3

et al. 2020

View full text Add to dashboard Cite

Voltage-gated potassium channels (K V s) perform vital physiological functions and are targets in different disorders ranging from ataxia and arrhythmia to autoimmune diseases. An important issue is the search for and production of selective ligands of these channels. Peptide toxins found in scorpion venom named KTx excel in both potency and selectivity with respect to some potassium channel isoforms, which may present only minute differences in their structure. Despite several decades of research the molecular determinants of KTx selectivity are still poorly understood. Here we analyze MeKTx13-3 (Kalium ID: α-KTx 3.19) from the lesser Asian scorpion Mesobuthus eupeus , a high-affinity K V 1.1 blocker (IC 50 ~2 nM); it also affects K V 1.2 (IC 50 ~100 nM), 1.3 (~10 nM) and 1.6 (~60 nM). By constructing computer models of its complex with K V 1.1–1.3 channels we identify specific contacts between the toxin and the three isoforms. We then perform mutagenesis to disturb the identified contacts with K V 1.1 and 1.2 and produce recombinant MeKTx13-3_AAAR, which differs by four amino acid residues from the parent toxin. As predicted by the modeling, this derivative shows decreased activity on K V 1.1 (IC 50 ~550 nM) and 1.2 (~200 nM). It also has diminished activity on K V 1.6 (~1500 nM) but preserves K V 1.3 affinity as measured using the voltage-clamp technique on mammalian channels expressed in Xenopus oocytes. In effect, we convert a selective K V 1.1 ligand into a new specific K V 1.3 ligand. MeKTx13-3 and its derivatives are attractive tools to study the structure-function relationship in potassium channel blockers.

show abstract

Targeting the Mitochondrial Potassium Channel Kv1.3 to Kill Cancer Cells: Drugs, Strategies, and New Perspectives

Cited by 16 publications

References 117 publications

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Mitochondrial Kv1.3: a New Target in Cancer Biology?

Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3

Contact Info

Product

Resources

About

Targeting the Mitochondrial Potassium Channel Kv1.3 to Kill Cancer Cells: Drugs, Strategies, and New Perspectives

Cited by 16 publications

References 117 publications

Discovery of KV1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Discovery of KV1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Mitochondrial Kv1.3: a New Target in Cancer Biology?

Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3

Contact Info

Product

Resources

About

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges