Discovery and evaluation of nNa v 1.5 sodium channel blockers with potent cell invasion inhibitory activity in breast cancer cells

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design
  • Humans
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism*
  • Neoplasm Invasiveness / prevention & control*
  • Neoplasm Metastasis / prevention & control
  • Quantitative Structure-Activity Relationship
  • Voltage-Gated Sodium Channel Blockers / chemical synthesis
  • Voltage-Gated Sodium Channel Blockers / chemistry
  • Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

  • Antineoplastic Agents
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Voltage-Gated Sodium Channel Blockers