Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective Kv7.1 (KCNQ1) potassium channel activator

Mattmann, Margrith E.; Yu, Haibo; Lin, Zhihong; Xu, Kaiping; Huang, Xiaofang; Long, Shunyou; Wu, Meng; McManus, Owen B.; Engers, Darren W.; Le, Uyen; Li, Min; Lindsley, Craig W.; Hopkins, Corey R.

doi:10.1016/j.bmcl.2012.07.060

Cited by 62 publications

(57 citation statements)

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“…ML277 was identified as a KCNQ1 activator in a high-throughput screen for KCNQ1 potassium channel modulators using the NIH Molecular Libraries Small Molecule Repository compound collection (21). ML277 stereo-selectively activates KCNQ1 channels with EC 50 at submicromolar range.…”

Section: Resultsmentioning

confidence: 99%

“…ML277 stereo-selectively activates KCNQ1 channels with EC 50 at submicromolar range. The compound is highly selective against other KCNQ channels by as much as 100-fold over KCNQ2 and KCNQ4 potassium channels (21) and against other heart ion channels including the human ether-a-go-go related gene (hERG), Nav1.5, and Cav1.2 (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we used a potent KCNQ1 modulator, ML277 (21), to examine how differential coassembly with KCNE1 modulates the pharmacological properties of KCNQ1-KCNE1 complexes. By testing (KCNQ1) 4 (KCNE1) n channels in a heterologous expression system and comparing these results with I Ks currents in differentiated human cardiomyocytes, we identified differential pharmacological sensitivity of KCNQ1-KCNE1 complexes at different KCNE1 expression levels.…”

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Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Lin

Mattmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-gated KCNQ1 (Kv7.1) potassium channels are expressed abundantly in heart but they are also found in multiple other tissues. Differential coassembly with single transmembrane KCNE beta subunits in different cell types gives rise to a variety of biophysical properties, hence endowing distinct physiological roles for KCNQ1-KCNEx complexes. Mutations in either KCNQ1 or KCNE1 genes result in diseases in brain, heart, and the respiratory system. In addition to complexities arising from existence of five KCNE subunits, KCNE1 to KCNE5, recent studies in heterologous systems suggest unorthodox stoichiometric dynamics in subunit assembly is dependent on KCNE expression levels. The resultant KCNQ1-KCNE channel complexes may have a range of zero to two or even up to four KCNE subunits coassembling per KCNQ1 tetramer. These findings underscore the need to assess the selectivity of small-molecule KCNQ1 modulators on these different assemblies. Here we report a unique small-molecule gating modulator, ML277, that potentiates both homomultimeric KCNQ1 channels and unsaturated heteromultimeric (KCNQ1) 4 (KCNE1) n (n < 4) channels. Progressive increase of KCNE1 or KCNE3 expression reduces efficacy of ML277 and eventually abolishes ML277-mediated augmentation. In cardiomyocytes, the slowly activating delayed rectifier potassium current, or I Ks , is believed to be a heteromultimeric combination of KCNQ1 and KCNE1, but it is not entirely clear whether I Ks is mediated by KCNE-saturated KCNQ1 channels or by channels with intermediate stoichiometries. We found ML277 effectively augments I Ks current of cultured human cardiomyocytes and shortens action potential duration. These data indicate that unsaturated heteromultimeric (KCNQ1) 4 (KCNE1) n channels are present as components of I Ks and are pharmacologically distinct from KCNE-saturated KCNQ1-KCNE1 channels.cardiac physiology | drug | long QT | pharmacology

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Lin

Mattmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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122

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“…However, ion flux assays are performed under less physiologically relevant conditions [7,8] and may underestimate drug blocking potency [8] . Recent advance in automated electrophysiology technology has provided platforms such as IonWorks Quattro that can generate data with high information content and good quality at higher throughput [9][10][11] . This permits applications of automated electrophysiology in primary screening.…”

Section: Introductionmentioning

confidence: 99%

Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay

Zou

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: hERG potassium channels display miscellaneous interactions with diverse chemical scaffolds. In this study we assessed the hERG inhibition in a large compound library of diverse chemical entities and provided data for better understanding of the mechanisms underlying promiscuity of hERG inhibition.Methods: Approximately 300 000 compounds contained in Molecular Library Small Molecular Repository (MLSMR) library were tested. Compound profiling was conducted on hERG-CHO cells using the automated patch-clamp platform-IonWorks Quattro TM .Results: The compound library was tested at 1 and 10 μmol/L. IC 50 values were predicted using a modified 4-parameter logistic model. Inhibitor hits were binned into three groups based on their potency: high (IC 50 <1 μmol/L), intermediate (1 μmol/L< IC 50 <10 μmol/L), and low (IC 50 >10 μmol/L) with hit rates of 1.64%, 9.17% and 16.63%, respectively. Six physiochemical properties of each compound were acquired and calculated using ACD software to evaluate the correlation between hERG inhibition and the properties: hERG inhibition was positively correlative to the physiochemical properties ALogP, molecular weight and RTB, and negatively correlative to TPSA. Conclusion: Based on a large diverse compound collection, this study provides experimental evidence to understand the promiscuity of hERG inhibition. This study further demonstrates that hERG liability compounds tend to be more hydrophobic, high-molecular, flexible and polarizable.Keywords: hERG; high-throughput screening; MLSMR library; automated electrophysiology; cardiotoxicity Acta Pharmacologica Sinica (2016) 37: 111−123; doi: 10.1038/aps.2015 Original Article IntroductionThe acquired long QT syndrome is both a threat to public health and a major stumbling block for drug development [1] . It is most often caused through unintended blockade of the cardiac repolarizing potassium channel, I Kr , encoded by the Human Ether-a-go-go related gene (hERG) [2] . Blockade of hERG channel was found to be associated with an increased duration of ventricular repolarization and prolongation of QT interval (long QT syndrome, or LQTS). hERG potassium channel displays promiscuous interactions with diverse chemical scaffolds [3] . Structurally and functionally unrelated drugs have been shown to block hERG channel, and some of these agents, including terfenadine, astemizole, droperidol and cisapride, etc, have been withdrawn from the market due to their potential to predispose individuals to sudden cardiac death. Due to the important implications in both drug discovery [4] and clinical practice, evaluation of hERG liability has been required for any new chemical entities by regulatory agencies according to the ICH S7B guideline since 2005 [5] .Manual patch clamp method is considered as gold standard for ion channel functional evaluation [6] . However the method is very labor-intensive with low throughput, and thus its application in drug discovery is limited. Ion flux assays with surrogate ions of Rubidium (Rb + ) or Thallium (Tl + ) have ...

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“…However, one Kv7.1 mutation is reported to disrupt R-L3 binding and, thereby, channel activation [20]. Recently, further Kv7.1 activators have been described [22][23][24][25]. Potent activators of Kv7.4 include BMS-204352 [26], but often lack selectivity.…”

Section: Introductionmentioning

confidence: 99%

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels

Matschke

Piccini²,

Schubert

et al. 2016

Cell Physiol Biochem

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Background/Aims: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K⁺ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. Methods: Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. Results: We show that currents carried by Kv7.1 (EC₅₀ = 1.48 μM), Kv7.1/KCNE1 (EC₅₀ = 4.9 μM), and Kv7.4 (EC₅₀ = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1.Conclusion: Rottlerin or an optimized derivative holds a potential as QT interval correcting drug.

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Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective Kv7.1 (KCNQ1) potassium channel activator

Cited by 62 publications

References 8 publications

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels

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