Help Privacy Policy Disclaimer
  Advanced SearchBrowse


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

Toplak, Z., Hendrickx, L. A., Abdelaziz, R., Shi, X., Peigneur, S., Tomasic, T., et al. (2022). Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment. Medicinal Research Reviews. doi:10.1002/med.21808.

Item is


show Files
hide Files
Medicinal Research Reviews - 2021 - Toplak.pdf (Publisher version), 5MB
Medicinal Research Reviews - 2021 - Toplak.pdf
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
Copyright Info:




Toplak, Z., Author
Hendrickx, L. A., Author
Abdelaziz, Reham1, 2, Author           
Shi, X.1, 2, Author
Peigneur, S., Author
Tomasic, T., Author
Tytgat, J., Author
Peterlin-Masic, L., Author
Pardo, Luis A.1, 2, Author           
1Oncophysiology, Max Planck Institute of Experimental Medicine, Max Planck Society, Hermann-Rein-Str. 3, 37075 Göttingen, DE, ou_2559695              
2Research Group of Oncophysiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, Göttingen, DE, ou_3350304              


Free keywords: Eag1 Herg arrhythmia cancer potassium channels rational drug design
 Abstract: 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 (KV 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.


Language(s): eng - English
 Dates: 2021-05-042022-01
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1002/med.21808
 Degree: -



Legal Case


Project information

show hide
Project name : Jan Tytgat was supported by grants G0E7120N, GOC2319N and GOA4919N (FWO-Vlaanderen), and grant CELSA/17/047 (KU Leuven). Steve Peigneur was supported by grant PDM/19/164 (KU Leuven). Lucija Peterlin-Mašič was supported by grants J1-9192, N1-0098, P1-0208 (ARRS), and grant CELSA 005-1/2017 (University of Ljubljana). Luis A. Pardo acknowledges the support of the Max-Planck Society, and the Göttingen Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften (GGNB) (RA). This project has received funding from the from the Eur Union through Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 813834-PHIONIC-H2020-MSCA-ITN-2018. Open access funding enabled and organized by Projekt DEAL.
Grant ID : -
Funding program : -
Funding organization : -
Project name : pHioniC
Grant ID : 813834
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

Source 1

Title: Medicinal Research Reviews
  Other : Med. Res. Rev.
Source Genre: Journal
Publ. Info: New York, N.Y. : Wiley
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 0198-6325
CoNE: https://pure.mpg.de/cone/journals/resource/954925492909