Identification of New Mono/Dihydroxynaphthoquinone as Lead Agents That Inhibit the Growth of Refractive and Triple-Negative Breast Cancer Cell Lines
journal contributionposted on 19.06.2019, 08:29 by Richard Schroeder, Mary Sfondouris, Navneet Goyal, Rajesh Komati, Achira Weerathunga, Cory Gettridge, Cheryl L. Klein Stevens, Frank E. Jones, Jayalakshmi Sridhar
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.
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HER 2Δ16-expressing MCF -7 cellsIC 50 0.29compoundIC 50 0.51patient survivaltumor survival pathwaysHER 2 kinase inhibitorsIC 50 valuesHER 2Δ16.Compound 7HER 2 autophosphorylationtrastuzumab-resistant HER 2 oncogenic isoformTriple-Negative Breast Cancer Cell Lines Human epidermal growth factor receptor 2breast tumor cellsnaphthoquinone derivativesLead Agentsbreast cancer cell linesinhibition profile1.76 μ MHER 2EGFR2.92 μ Mbreast cancerscell deathHER 2-expressing MCF -7 cells