title: Identification of quinones as HER2 inhibitors for the treatment of trastuzumab resistant breast cancer.
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.
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, United States. Electronic address: jsridhar@xula.edu.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, 6400 Freret Street, 2000 Percival Stern Hall, New Orleans, LA 70118, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Sfondouris
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, United States.
authors.forename: Melyssa R
authors.initials: MR
authors.lastname: Bratton
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, United States.
authors.forename: Thuy-Linh K
authors.initials: TL
authors.lastname: Nguyen
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, United States.
authors.forename: Ian
authors.initials: I
authors.lastname: Townley
authors.affiliation: Ogden College of Science and Engineering, Western Kentucky University, 1906 College Heights Boulevard #11075, Bowling Green, KY 42101-1075, United States.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Klein Stevens
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, 6400 Freret Street, 2000 Percival Stern Hall, New Orleans, LA 70118, United States.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Jones
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Breast cancer; Docking studies; Emodin; HER2Δ16; Human epidermal growth factor receptor 2 (HER2); Phosphorylation; Quinones; Tyrosine kinase