Estrogen receptor(ER)αis expressed in a subset of patient-derived acute myeloid leukemia(AML)cells,whereas Akt is predominantly expressed in most types of AML.Targeting AML with dual inhibitors is a novel approach to...Estrogen receptor(ER)αis expressed in a subset of patient-derived acute myeloid leukemia(AML)cells,whereas Akt is predominantly expressed in most types of AML.Targeting AML with dual inhibitors is a novel approach to combat the disease.Herein,we examined a novel small molecule,3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),capable of targeting AML cells by inhibiting ERαand Akt kinase.The chemical properties of SBL-060 were identified by proton nuclear magnetic resonance(^(1)H-NMR),^(13)C-NMR,and mass spectroscopy.In silico docking was performed using an automated protocol with AutoDock-VINA.THP-1 and HL-60 cell lines were differentiated using phorbol 12-myristate 13-acetate.ERαinhibition was assessed using ELISA.The MTT assay assessed cell viability.Flow cytometry was performed for cell cycle,apoptosis,and p-Akt analyses.Chemical analysis identified the compound as 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one,which showed high binding efficacy toward ER,with aΔG_(binding) score of−7.4 kcal/mol.SBL-060 inhibited ERα,exhibiting IC50 values of 448 and 374.3 nM in THP-1 and HL-60 cells,respectively.Regarding inhibited cell proliferation,GI50 values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells,respectively.In addition,a dose-dependent increase in sub G_(0)/G_(1) phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in both cell types.SBL-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 cells.Our results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Akt kinase,warranting further preclinical evaluations.展开更多
文摘Estrogen receptor(ER)αis expressed in a subset of patient-derived acute myeloid leukemia(AML)cells,whereas Akt is predominantly expressed in most types of AML.Targeting AML with dual inhibitors is a novel approach to combat the disease.Herein,we examined a novel small molecule,3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),capable of targeting AML cells by inhibiting ERαand Akt kinase.The chemical properties of SBL-060 were identified by proton nuclear magnetic resonance(^(1)H-NMR),^(13)C-NMR,and mass spectroscopy.In silico docking was performed using an automated protocol with AutoDock-VINA.THP-1 and HL-60 cell lines were differentiated using phorbol 12-myristate 13-acetate.ERαinhibition was assessed using ELISA.The MTT assay assessed cell viability.Flow cytometry was performed for cell cycle,apoptosis,and p-Akt analyses.Chemical analysis identified the compound as 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one,which showed high binding efficacy toward ER,with aΔG_(binding) score of−7.4 kcal/mol.SBL-060 inhibited ERα,exhibiting IC50 values of 448 and 374.3 nM in THP-1 and HL-60 cells,respectively.Regarding inhibited cell proliferation,GI50 values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells,respectively.In addition,a dose-dependent increase in sub G_(0)/G_(1) phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in both cell types.SBL-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 cells.Our results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Akt kinase,warranting further preclinical evaluations.
