Drug Screening of Potential Multiple Target Inhibitors for Estrogen Receptor-α-positive Breast Cancer

In Vivo. Mar-Apr 2021;35(2):761-777. doi: 10.21873/invivo.12317.


Background/aim: Estrogen receptor α (ERα) antagonist is the most common treatment for ERα-positive breast cancer. However, compensatory signaling contributes to resistance to ERα antagonists. Thus, to explore the potential agents for targeting compensatory signaling, we screened multiple target inhibitors for breast cancer treatment.

Materials and methods: We attempted to build a structure-based virtual screening model that can find potential compounds and assay the anticancer ability of these drugs by overall cell survival assay. The downstream compensatory phosphorylated signaling was measured by immunoblotting.

Results: Hamamelitannin and glucocheirolin were hits for ERα, phosphoinositide 3-kinase (PI3K), and KRAS proto-oncogene, GTPase (KRAS), which were active against estrogen and epidermal growth factor-triggered proliferation. Additionally, we select aminopterin as a hit for ERα, PI3K, KRAS, and SRC proto-oncogene, non-receptor tyrosine kinase (SRC) with inhibitory activities toward AKT serine/threonine kinase 1 (AKT) and mitogen-activated protein kinase kinase (MEK) signaling.

Conclusion: Our structure-based virtual screening model selected hamamelitannin, glucocheirolin, aminopterin, and pemetrexed as compounds that may act as potential inhibitors for improving endocrine therapies for breast cancer.

Keywords: ER+ breast cancer; Multiple inhibitors; aminopterin.

MeSH terms

  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Early Detection of Cancer
  • Estrogen Receptor alpha / genetics
  • Female
  • Humans
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptors, Estrogen


  • Estrogen Receptor alpha
  • Receptors, Estrogen
  • Proto-Oncogene Proteins c-akt