6533b82dfe1ef96bd1292031
RESEARCH PRODUCT
(+)-Dehydroabietylamine derivatives target triple-negative breast cancer.
Iram FatimaMichele ConnellyTaotao LingMy TranGustavo A. Miranda-carboniMiguel A. GonzálezRachael K. WoodLekh Nath S. GautamFatima Rivassubject
medicine.drug_classPhenotypic screeningApoptosisTriple Negative Breast NeoplasmsPharmacologyCarnosolchemistry.chemical_compoundStructure-Activity RelationshipBreast cancerCell Line TumorDrug DiscoverymedicineHumansTriple-negative breast cancerCell ProliferationPharmacologyBiological ProductsDose-Response Relationship DrugMolecular StructureCell growthDrug discoveryOrganic ChemistryStereoisomerismGeneral MedicineTriple Negative Breast Neoplasmsmedicine.diseaseAntineoplastic Agents PhytogenicchemistryEstrogenAbietanesMCF-7 CellsFemaleDrug Screening Assays Antitumordescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-09-01 | European journal of medicinal chemistry |