Title
Identification of New Mono/Dihydroxynaphthoquinone as Lead Agents That Inhibit the Growth of Refractive and Triple-Negative Breast Cancer Cell Lines.
Funding Source
Institute of Molecular and Cell Biology, Louisiana Biomedical Research Network, National Institutes of Health, U.S. Department of Defense
Grant Number
2G12MD007595-06, 8P20GM103424, TL4M118968, W81XWH-11-1-0105
Department
Department of Chemistry
Document Type
Article
Publication Date
6-19-2019
Abstract
Human epidermal growth factor receptor 2 (HER2) is overexpressed in nearly 20-30% of breast cancers and is associated with metastasis resulting in poor patient survival and high recurrence. The dual EGFR/HER2 kinase inhibitor lapatinib has shown promising clinical results, but its limitations have also led to the resistance and activation of tumor survival pathways. Following our previous investigation of quinones as HER2 kinase inhibitors, we synthesized several naphthoquinone derivatives that significantly inhibited breast tumor cells expressing HER2 and trastuzumab-resistant HER2 oncogenic isoform, HER2Δ16. Two of these compounds were shown to be more effective than lapatinib at the inhibition of HER2 autophosphorylation of Y1248. Compounds 7 (5,8-dihydroxy-2-methylnaphthalene-1,4-dione) and 9 (2-(bromomethyl)-5,8-dihydroxynaphthalene-1,4-dione) inhibited HER2-expressing MCF-7 cells (IC50 0.29 and 1.76 μM, respectively) and HER2Δ16-expressing MCF-7 cells (IC50 0.51 and 1.76 μM, respectively). Compound 7 was also shown to promote cell death in multiple refractory breast cancer cell lines with IC50 values ranging from 0.12 to 2.92 μM. These compounds can function as lead compounds for the design of a new series of nonquinonoid structural compounds that can maintain a similar inhibition profile.
Recommended Citation
Schroeder, R; Sfondouris, M.; Goyal, N.; Komati, R.; Weerathunga, A.; Geetridge, C.; Stevens., C. L.; Jones, F. E.; and Sridhar, Jayalakshmi, "Identification of New Mono/Dihydroxynaphthoquinone as Lead Agents That Inhibit the Growth of Refractive and Triple-Negative Breast Cancer Cell Lines." (2019). Faculty and Staff Publications. 94.
https://digitalcommons.xula.edu/fac_pub/94
Comments
DOI: 10.1021/acsomega.9b00929
Funding text
The authors acknowledge the financial support for this work by the Department of Defense Award W81XWH-11-1-0105 and the Louisiana Biomedical Research Network NIH award [8P20GM103424]. The authors acknowledge the additional support of the NIH BUILD Grant [TL4M118968], the Louisiana Cancer Research Consortium, the Cell and Molecular Biology Core NIH-RCMI [2G12MD007595-06], and the Center for Undergraduate Research at the Xavier University of Louisiana. The authors also thank the University of Texas, Austin Mass Spectrometry Facility for the HRMS analysis of our samples.