title: (+)-Dehydroabietylamine derivatives target triple-negative breast cancer.
abstract: Breast cancer remains the leading cause of cancer-related death among women. The invasive triple-negative subtype is unresponsive to estrogen therapy, and few effective treatments are available. In search of new chemical scaffolds to target this disease, we conducted a phenotypic screen against the human breast carcinoma cell lines MDA-MB-231, MA11, and MCF-7 using terrestrial natural products. Natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells were further studied; herein we focused on the abietanes. The activity of the abietane carnosol prompted us to generate a focus library from the readily available (+)-dehydroabietylamine. The lead compound 61 displayed a promising EC50 of 9.0 μM against MDA-MB-231 and our mechanistic studies indicate it induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of PARP. Here we describe our current progress towards this promising therapeutic candidate.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Taotao
authors.initials: T
authors.lastname: Ling
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: My
authors.initials: M
authors.lastname: Tran
authors.affiliation: Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Lekh Nath
authors.initials: LN
authors.lastname: Gautam
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Rachael K
authors.initials: RK
authors.lastname: Wood
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Iram
authors.initials: I
authors.lastname: Fatima
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Miranda-Carboni
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA. Electronic address: Fatima.rivas@stjude.org.
authors.forename: Fatima
authors.initials: F
authors.lastname: Rivas
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; C000600819:dehydroabietylamine
keywords: (+)-Dehydroabietylamine; Abietane; Apoptosis; Breast cancer; Triple-negative