Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment

Toplak, Žan; Hendrickx, Louise Antonia; Abdelaziz, Reham; Shi, Xiaohong; Peigneur, Steve; Tomašič, Tihomir; Tytgat, Jan; Mašič, Lucíja Peterlin; Pardo, Luis A.

doi:10.1002/med.21808

Cited by 23 publications

(24 citation statements)

References 230 publications

(585 reference statements)

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“…Recently, researchers have turned to hiPSC-derived-CMs as an excellent alternative and a more reliable tool in the earliest stages of drug development to detect side effects of a new potential therapeutic agent that may cause prolongation of the QT interval before it is used in animal studies and clinical trials [ 323 ]. In addition, hiPSC allows us to study the behavior of ion channels in real CMs rather than in cell lines that are not myocytes and overexpress the potassium channel because of the response to compounds tested with hiPSC-derived-CMs in vitro is similar to that of the human body [ 324 ]. The effects of new drugs can be assessed in several ways, including electrophysiological responses using microelectrode arrays (MEAs), patch-clamp, or Ca 2+ oscillation measurements.…”

Section: Drug Testing and Drugs Development Using Hipsc-derived-cmsmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective

Bekhite

Schulze

2021

Cells

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A comprehensive understanding of the pathophysiology and cellular responses to drugs in human heart disease is limited by species differences between humans and experimental animals. In addition, isolation of human cardiomyocytes (CMs) is complicated because cells obtained by biopsy do not proliferate to provide sufficient numbers of cells for preclinical studies in vitro. Interestingly, the discovery of human-induced pluripotent stem cell (hiPSC) has opened up the possibility of generating and studying heart disease in a culture dish. The combination of reprogramming and genome editing technologies to generate a broad spectrum of human heart diseases in vitro offers a great opportunity to elucidate gene function and mechanisms. However, to exploit the potential applications of hiPSC-derived-CMs for drug testing and studying adult-onset cardiac disease, a full functional characterization of maturation and metabolic traits is required. In this review, we focus on methods to reprogram somatic cells into hiPSC and the solutions for overcome immaturity of the hiPSC-derived-CMs to mimic the structure and physiological properties of the adult human CMs to accurately model disease and test drug safety. Finally, we discuss how to improve the culture, differentiation, and purification of CMs to obtain sufficient numbers of desired types of hiPSC-derived-CMs for disease modeling and drug development platform.

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Section: Drug Testing and Drugs Development Using Hipsc-derived-cmsmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective

Bekhite

Schulze

2021

Cells

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“…Validation of the final merged K V 10.1 structure-based pharmacophore model was performed by screening against two libraries. The first library contained 15 compounds with known IC 50 values for K V 10.1 inhibition and a known binding site in the channel pore (Supporting Information Table S1) [17]. The second library contained compounds ('decoys') that are not likely to inhibit K V 10.1.…”

Section: Virtual Library Preparationmentioning

confidence: 99%

“…Ligands that have been reported to inhibit K V 10.1, but where the mechanism of action is not through the block of the potassium ion flux by binding to the central cavity of the channel, should therefore not fit our pharmacophore model. Our model was tested on such a virtual library (Supporting Information Table S3) that was constructed from ligands collected in a review article [17], with the addition of our newly identified set of K V 10.1 inhibitors [53]. The pharmacophore model identified 16 of 61 active compounds.…”

Section: Creation Of the Merged Structure-based Pharmacophore Modelmentioning

confidence: 99%

“…The reason for this is the great interest in blocking the cardiac hERG channels in drug development, as hERG inhibition is an undesirable side-effect that results in safety concerns. In addition, the number of known K V 10.1 inhibitors is very small, but a better understanding of K V 10.1 inhibition and binding of known ligands might lead to improved design strategies and the development of new anticancer drugs that act as K V 10.1 inhibitors [17].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics-Derived Pharmacophore Model Explaining the Nonselective Aspect of KV10.1 Pore Blockers

Merzel

Pardo

Mašič

et al. 2021

IJMS

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The KV10.1 voltage-gated potassium channel is highly expressed in 70% of tumors, and thus represents a promising target for anticancer drug discovery. However, only a few ligands are known to inhibit KV10.1, and almost all also inhibit the very similar cardiac hERG channel, which can lead to undesirable side-effects. In the absence of the structure of the KV10.1–inhibitor complex, there remains the need for new strategies to identify selective KV10.1 inhibitors and to understand the binding modes of the known KV10.1 inhibitors. To investigate these binding modes in the central cavity of KV10.1, a unique approach was used that allows derivation and analysis of ligand–protein interactions from molecular dynamics trajectories through pharmacophore modeling. The final molecular dynamics-derived structure-based pharmacophore model for the simulated KV10.1–ligand complexes describes the necessary pharmacophore features for KV10.1 inhibition and is highly similar to the previously reported ligand-based hERG pharmacophore model used to explain the nonselectivity of KV10.1 pore blockers. Moreover, analysis of the molecular dynamics trajectories revealed disruption of the π–π network of aromatic residues F359, Y464, and F468 of KV10.1, which has been reported to be important for binding of various ligands for both KV10.1 and hERG channels. These data indicate that targeting the KV10.1 channel pore is also likely to result in undesired hERG inhibition, and other potential binding sites should be explored to develop true KV10.1-selective inhibitors as new anticancer agents.

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“…Ether à‐go‐go (Eag1) channels, a subtype of voltage‐dependent potassium channels, have also been shown to be important in the development of cancer types such as prostate, melanoma, breast, neuroblastoma and cervical cancer by associating it with cell proliferation (Bernal‐Ramos et al., 2017; Farias et al., 2004; Meyer & Heinemann, 1998; Meyer et al., 1999; Ouadid‐Ahidouch et al., 2001). These studies show that Eag1 channels can be used as biomarkers for early diagnosis of cancer and as new targets for cancer treatment (Rodríguez‐Rasgado et al., 2012; Toplak et al., 2021).…”

Section: Introductionmentioning

confidence: 99%

Effect of imipramine on ether à‐go‐go potassium channel (Kv1.10) expression in DU145 prostate cancer cells

et al. 2021

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In recent studies, it has been reported that ion channels play an important role in cancer formation. Therefore, it is possible that the use of pharmacological agents targeting ion channels will allow the development of new strategies for cancer treatment. In this study, we investigate the effect of imipramine on Eag1 channel expression in DU145 prostate cancer cells. Culture cells were divided into 4 groups as the control, 10, 50 and 75 µM imipramine. Eag1 channel currents and conductivity were determined by whole‐cell patch‐clamp technique and gene expression by real time‐polymerase chain reaction (RT‐PCR). Current records were taken before (at 0th minute, as control) and 10 min after imipramine administration to the cells. It was observed that all three doses of imipramine significantly reduced Eag1 currents and conductivity compared with the control. However, the differences between dose groups were not significant. Similarly, Eag1 channel protein expression was found to be significantly reduced for all three doses of imipramine compared with the control group, but there was no significant difference in gene expression between dose groups. Obtained results suggested that imipramine has the potential to be used as a pharmacological agent targeting the Eag1 channel in the treatment of prostate cancer.

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Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment

Cited by 23 publications

References 230 publications

Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective

Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective

Molecular Dynamics-Derived Pharmacophore Model Explaining the Nonselective Aspect of KV10.1 Pore Blockers

Effect of imipramine on ether à‐go‐go potassium channel (Kv1.10) expression in DU145 prostate cancer cells

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