作者: Meng, Chao ; Wort, Stephen J ; Humbert, Marc ; Perros, Frederic ; Adcock, Ian M ; Garfield, Benjamin E ; Montani, David ; Zhu, Jie ; Price, Laura C ; Dorfmuller, Peter ; Shao, Dongmin

BACKGROUNDDexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an important concept in PAH disease therapy, and further to its anti-proliferative effects, we sought to explore whether dexamethasone augments pulmonary arterial smooth muscle cell (PASMC) apoptosis.METHODSAnalysis of apoptosis markers (caspase 3, in-situ DNA fragmentation) and NF-κB (p65 and phospho-IKK-α/β) activation was performed on lung tissue from rats with monocrotaline (MCT)-induced pulmonary hypertension (PH), before and after day 14-28 treatment with dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH model and from normal human lung following lung cancer surgery. Following stimulation with TNF-α (10 ng/ml), the effects of dexamethasone (10(-8)-10(-6) M) and IKK2 (NF-κB) inhibition (AS602868, 0-3 μM (0-3×10(-6) M) on IL-6 and CXCL8 release and apoptosis was determined by ELISA and by Hoechst staining. NF-κB activation was measured by TransAm assay.RESULTSDexamethasone treatment of rats with MCT-induced PH in vivo led to PASMC apoptosis as displayed by increased caspase 3 expression and DNA fragmentation. A similar effect was seen in vitro using TNF-α-simulated human and rat PASMC following both dexamethasone and IKK2 inhibition. Increased apoptosis was associated with a reduction in NF-κB activation and in IL-6 and CXCL8 release from PASMC.CONCLUSIONSDexamethasone exerted reverse-remodelling effects by augmenting apoptosis and reversing inflammation in PASMC possibly via inhibition of NF-κB. Future PAH therapies may involve targeting these important inflammatory pathways.

2014-06-01·Bioorganic & Medicinal Chemistry Letters4区 · 医学

Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKβ inhibitors

4区 · 医学

Article

作者: Kim, Myung-Hwa ; Chun, Kwangwoo ; Yang, Jee Sun ; Han, Gyoonhee ; Kim, Hyuntae ; Joe, Bo-Young ; Kang, Jong Soon ; Park, Chun-Ho ; Kim, Hye Yun ; Lee, Jangik I ; Lee, Chulho

Inactivation of the NF-κB signaling pathway by inhibition of IKKβ is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKβ inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKβ was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1μM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

2011-07-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868

4区 · 医学

Article

作者: Delphine Demangel ; Charles Dumontet ; Stéphanie Herveau ; Michel Dreano ; Emeline Cros-Perrial ; Lars Petter Jordheim ; Julie A. Vendrell ; Adriana Plesa ; Céline Keime

PURPOSEThe need for new treatment options for acute myeloid leukemia (AML) is increasing. AS602868 is a novel investigational drug with reported activity on AML cells.METHODSWe studied gene expression profiles in AML blasts exposed to AS602868 in order to better understand its mechanism of action. We analyzed the in vitro cytotoxicity of AS602868 alone or in combination with daunorubicin, etoposide or cytarabine. To document AS602868-induced IKK2 inhibition in fresh AML cells, a flow cytometry analysis of IκB was performed. Finally, the effect of AS602868 on gene expression in fresh AML cells was analyzed.RESULTSThe results show that AML cells are globally as sensitive to AS602868 as they are to cytarabine, with large interindividual variations. Combinations with conventional antileukemic agents showed enhanced cytotoxic activity in subsets of patients. IKK2 appeared to be effectively inhibited by 100 μM AS602868 in fresh leukemic cells. Gene expression profiling and gene ontology analyses identified several groups of genes induced/inhibited by exposure to AS602868 and/or exhibiting a correlation with sensitivity to this agent in vitro. Of note, the expression of several genes related to immune function was found to be significantly altered after exposure to AS602868.CONCLUSIONThese data suggest that AS602868 is cytotoxic against fresh human AML blasts and provide insights regarding the mechanisms of cytotoxicity.

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适应症	最高研发状态	国家/地区	公司	日期
血液肿瘤	临床1期	美国	Merck Serono SA	-
炎症	临床1期	美国	-	-
多发性硬化症	临床1期	瑞士	Merck Serono SA	-
多发性硬化症	临床1期	美国	Celgene Corp.	-
多发性硬化症	临床1期	瑞士	Merck Serono SA	-
多发性硬化症	药物发现	美国	Celgene Corp.	-