Identification of quinones as HER2 inhibitors for the treatment of trastuzumab resistant breast cancer |
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| Affiliation: | 1. Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, United States;2. Department of Cell and Molecular Biology, Tulane University, 6400 Freret Street, 2000 Percival Stern Hall, New Orleans, LA 70118, United States;3. College of Pharmacy, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, United States;4. Ogden College of Science and Engineering, Western Kentucky University, 1906 College Heights Boulevard #11075, Bowling Green, KY 42101-1075, United States;1. Tandem Accelerator Laboratory, Institute of Nuclear Physics, N.C.S.R. “Demokritos”, Aghia Paraskevi, 15310 Athens, Greece;2. Department of Physics, National Technical University of Athens, Zografou Campus, 15780 Athens, Greece;3. Department of Physics, University of Ioannina, 45110 Ioannina, Greece;4. Department of Chemistry, Aristotle University, GR-54124 Thessaloniki, Greece;1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;2. Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;3. Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan |
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| Abstract: | HER2 overexpression is associated with aggressive breast cancer with high recurrence rate and poor patient prognosis. Treatment of HER2 overexpressing patients with the HER2 targeting therapy trastuzumab results in acquired resistance within a year. The HER2/EGFR dual kinase inhibitor lapatinib was shown to inhibit some trastuzumab resistant breast cancer cell lines and is currently in clinical trials. Our group has found two new quinone compounds that show excellent inhibition of breast tumor cells expressing HER2 or the trastuzumab resistant HER2 oncogenic isoform, HER2Δ16. Compound 4 ((1R,2S,3S)-1,2,3,5,8-pentahydroxy-1,2,3,4-tetrahydroanthracene-9,10-dione) and compound 5 (5,8-dihydroxy-2,3-bis(hydroxymethyl)naphthalene-1,4-dione) showed sub-micromolar inhibition potency against these cell lines. These compounds also inhibit auto-phosphorylation of the Y1248 and Y1068 residues of HER2 and EGFR, respectively. |
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| Keywords: | Human epidermal growth factor receptor 2 (HER2) HER2Δ16 Tyrosine kinase Emodin Quinones Phosphorylation Breast cancer Docking studies |
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