Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel

Yu, Zhiyi; Veldhoven, Jacobus P. D. van; Hart, Ingrid M. E. ’t; Kopf, Adrian H.; Heitman, Laura H.; IJzerman, Adriaan P.

doi:10.1016/j.ejmech.2015.10.032

Cited by 19 publications

(32 citation statements)

References 34 publications

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“… 77 − 79 Here, we evaluated the K v 11.1 channel interaction of the two gold complexes [1]Cl and [2]Cl and their ligands H 2 biqbpy1 and H 2 biqbpy2 at a single concentration (10 μM) in a [ 3 H]dofetilide displacement assay. 80 When a compound binds to the K v 11.1 channel, the binding of the reference hERG blocker [ 3 H]dofetilide is decreased, which is used to quantify the K v 11.1 binding efficiency of the tested compounds. As shown in Table 3 , all four compounds displaced [ 3 H]dofetilide from the channel albeit to different degrees.…”

Section: Resultsmentioning

confidence: 99%

“…This experiment was carried out according to a literature procedure. 80 Briefly, the cell membranes of HEK293 Kv 11.1 cells were collected. Then the loading of [ 3 H]astemizole on the cell membranes was performed by mixing membrane aliquots containing 30 μg of protein with 2 nM [ 3 H]dofetilide in a total volume of 100 μL of incubation buffer at 15 °C for 90 min.…”

Section: Methodsmentioning

confidence: 99%

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Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Zhou

Carbo-Bague

Siegler

et al. 2021

JACS Au

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In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1] + , two pyridyl rings coordinate to the metal via a Au–C bond (C ∧ N ∧ N ∧ C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2] + all four pyridyl rings of the ligand coordinate to the metal via a Au–N bond (N ∧ N ∧ N ∧ N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [ 3 H]dofetilide equally well from cell membranes expressing the K v 11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H 2 biqbpy2 and TrxR-inhibiting Au + ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au + ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Zhou

Carbo-Bague

Siegler

et al. 2021

JACS Au

Self Cite

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“…Similarly, a recent study investigated whether a novel allosteric modulator (LUF7346) of the voltage-gated K + channel, hERG, could be used to treat congenital and/or drug-induced forms of LQTS ( Sala et al, 2016b ). LUF7346 acts as a type-1 hERG activator by increasing the rapidly activating delayed rectifier K + current ( I Kr ) window and slowing I Kr deactivation in a voltage-dependent manner ( Yu et al, 2015 ). By genetically correcting hiPSCs that harbour the KCNQ1 mutation R190Q, a pair of isogenic lines (LQT1 corr /LQT1 R190Q ) was created, thereby eliminating the influence of genetic background on the drug response ( Sala et al, 2016b ).…”

Section: Primary Arrhythmic Diseasesmentioning

confidence: 99%

“…Treating LQT2 patients with molecules that activate I Kr is also of particular interest and several compounds have been identified that have a similar effect on I Kr but act through different mechanisms ( Yu et al, 2015 ). Matsa et al examined the response of hiPSC-CMs to two experimental K + -channel enhancers: nicorandil and PD-118057 ( Matsa et al, 2011 ).…”

Section: Primary Arrhythmic Diseasesmentioning

confidence: 99%

Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies

Brandão

Tabel

Atsma

et al. 2017

Disease Models &Amp; Mechanisms

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It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved.

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“…Activators interact with Kv11.1 at various sites , and some share overlapping high-affinity molecular determinants (Casis et al, 2006;Perry et al, 2007; with classical pore blockers. We have developed the negative allosteric modulator/activator LUF7244, which indeed is able to counteract drug-induced AP prolongation and proarrhythmia in vitro (Yu et al, 2015 and drug-induced ventricular arrhythmia in vivo (Qile et al, 2019). Specifically, application of 10 μM LUF7244 decreased the affinity of Kv11.1 for cisapride, astemizole, dofetilide, and sertindole by 4.0-, 3.8-, 3.2-, and 2.2-fold, respectively .…”

Section: Introductionmentioning

confidence: 99%

Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

Qile¹

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determines cardiac systolic/diastolic function, and abnormalities could result in cardiac arrhythmia and even sudden cardiac death (Hoffman and Cranefield, 1960).Chapter 1 2. Phase 1 is a phase of rapid repolarization beginning with rapid inactivation of voltage-gated Na + channels that aborts inward INa. At the same time, a transient outward K + current, Ito (Rudy, 2008), by activating voltage-gated K + channels briefly, leads to a slight negative shift of membrane potential (Santana et al., 2010; Grant, 2009). 3. Phase 2 is the plateau phase. The slow delayed rectifier K + current, IKs is slowly activated allowing K + efflux, which is partially balanced by the inward ICa,L activated at phase 0. Moreover, the increased concentration of intracellular Ca 2+ also activates Ca 2+ channels on the sarcoplasmic reticulum (SR), the so-called Ryanodine receptors, allowing Ca 2+ efflux move from SR to cytoplasm, a Ca 2+ activated Clcurrent (Hoffman, 1960) allowing Cl − into the cell, and ionic pumps like Na + -Ca 2+ exchanger and Na + -K + pump. All these ionic movements result in the membrane potential remaining almost constant with a low level of membrane repolarizing (Grant, 2009; Grunnet, 2010). 4. Phase 3 is the phase of rapid repolarization because L-type Ca 2+ channels close, while IKs remains activated and the negative change in membrane potential induces more K + currents, primarily the rapid delayed rectifier K + current (IKr) and the inward rectifier K + current (IK1). The strong outward K + current brings the membrane potential back to its resting value. The voltage-gated delayed rectifier K + channels close at ~-85 mV, while IK1 remains active and helps to maintain the resting membrane potential (Grant, 2009; Kubo et al., 2005). 5. Phase 4 represents the resting phase. The resting membrane potential is stable and more or less constant at ~-80 mV, resulting from perfect balance between influx of ions (e.g. Na + and Ca 2+ ) and efflux of ions (e.g. K + , Cland HCO3 -) (Santana, 2010; Morad and Tung, 1982). Among these ion channels, the potassium channel family is the largest branch. It can be broadly divided into two subfamilies by its transmembrane structure features: the six-transmembrane-helix voltage-gated potassium channel (Kv) and the two-transmembrane-helix inward rectifier potassium channel (KIR) (Ho et al., 1993).

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Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel

Cited by 19 publications

References 34 publications

Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies

Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

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