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Bioorg Med Chem. 2018 May 15;26(9):2428-2436. doi: 10.1016/j.bmc.2018.04.003. Epub 2018 Apr 3.

Discovery and evaluation of nNav1.5 sodium channel blockers with potent cell invasion inhibitory activity in breast cancer cells.

Author information

1
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294-1240, USA; Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, 1025 18th Street South, Birmingham, AL 35294-1240, USA.
2
Inserm UMR1069, Nutrition, Croissance et Cancer, Université de Tours, Faculté de médecine, 10 Boulevard Tonnellé, 37032 Tours, Cedex, France.
3
Inserm UMR1069, Nutrition, Croissance et Cancer, Université de Tours, Faculté de médecine, 10 Boulevard Tonnellé, 37032 Tours, Cedex, France; Institut Universitaire de France, 1, rue Descartes, 75231 Paris Cedex 05, France.
4
Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, 1808 7th Ave S, Birmingham, AL 35294-0012, USA.
5
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294-1240, USA; Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, 1025 18th Street South, Birmingham, AL 35294-1240, USA. Electronic address: svelu@uab.edu.
6
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294-1240, USA; Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, 1025 18th Street South, Birmingham, AL 35294-1240, USA. Electronic address: wbrou@uab.edu.

Abstract

Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be associated with metastatic behavior in a variety of human cancers. The neonatal isoform of the VGSC subtype, Nav1.5 (nNav1.5) is overexpressed in the highly aggressive human breast cancer cell line, MDA-MB-231. The activity of nNav1.5 is known to promote the breast cancer cell invasion in vitro and metastasis in vivo, and its expression in primary mammary tumors has been associated with metastasis and patient death. Metastasis development is responsible for the high mortality of breast cancer and currently there is no treatment available to specifically prevent or inhibit breast cancer metastasis. In the present study, a 3D-QSAR model is used to assist the development of low micromolar small molecule VGSC blockers. Using this model, we have designed, synthesized and evaluated five small molecule compounds as blockers of nNav1.5-dependent inward currents in whole-cell patch-clamp experiments in MDA-MB-231 cells. The most active compound identified from these studies blocked sodium currents by 34.9 ± 6.6% at 1 μM. This compound also inhibited the invasion of MDA-MB-231 cells by 30.3 ± 4.5% at 1 μM concentration without affecting the cell viability. The potent small molecule compounds presented here have the potential to be developed as drugs for breast cancer metastasis treatment.

KEYWORDS:

Breast cancer; Cancer cell invasion; Metastasis; Sodium current; Voltage-gated sodium channel; nNa(v)1.5

PMID:
29673714
PMCID:
PMC5935567
[Available on 2019-05-15]
DOI:
10.1016/j.bmc.2018.04.003
[Indexed for MEDLINE]

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