2.Application of tyrosine kinase inhibitors as a promising targeting treatment for myeloproliferative neoplasms --- review.
Journal of Experimental Hematology 2011;19(4):1064-1070
As well as playing vital roles in main cellular processes, such as abnormal proliferation, differentiation, survival, apoptosis, and a lot of tyrosine kinases (TK) are involved in oncogenesis. TK or components of their signal pathways have been found abnormal in many hematological malignancies. Therefore, tyrosine kinase inhibitors (TKI) have been provided a great deal of enthusiasm for development of therapy in myeloproliferative neoplasms (MPN). Representativity, the treatment of chronic myelogenous leukemia (CML) was revolutionary for the design of imatinib mesylate (IM), which is a BCR/ABL TKI. Subsequently, because of need for the resistance or intolerance, novel agents are being explored and imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 gene mutations. Recently, JAK2 inhibitor drugs are currently being tested in clinical trials. Here, the current review mainly focuses on the role of TK in classic MPN including CML, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), and advances of targeting these abnormalities with small molecule inhibitors.
Drug Delivery Systems
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Humans
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Myeloproliferative Disorders
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drug therapy
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Protein-Tyrosine Kinases
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antagonists & inhibitors
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metabolism
5.Advances in the study of inhibitors of kinases and nuclear factors for treating allergic asthma.
Ren-Ping LIU ; Ai-Min MENG ; Qi HOU
Acta Pharmaceutica Sinica 2012;47(6):689-695
Currently, about 300 million people worldwide are affected by asthma. Most of these sufferers inhale immunosuppressants (ie corticosteroids) and beta-adrenergic receptor agonists for their asthma treatment. However, about 5%-10% of patients of asthma have poor response to such treatment. Investigation of kinase signaling pathway and nuclear transcription factor as a target molecule in the treatment of allergic asthma has been the concern of scholars home and abroad. This paper reviewed inhibitors of kinase signaling pathway and nuclear transcription factors for the treatment of asthma.
Animals
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Asthma
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drug therapy
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enzymology
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Humans
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Mitogen-Activated Protein Kinases
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antagonists & inhibitors
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Phosphatidylinositol 3-Kinase
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antagonists & inhibitors
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Protein Kinase Inhibitors
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therapeutic use
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Protein-Tyrosine Kinases
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antagonists & inhibitors
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metabolism
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Signal Transduction
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Transcription Factors
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antagonists & inhibitors
8.Inhibitory effect of apatinib on HL-60 cell proliferation and its mechanism.
Shu LIANG ; Xiu-zhen TONG ; Li-wu FU
Journal of Southern Medical University 2011;31(5):871-874
OBJECTIVETo investigate the effect of apatinib, a small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, on the proliferation of human acute myeloid leukemia HL-60 cells and explore the possible mechanism.
METHODSMTT assay was used to assess the cytotoxicity of apatinib in HL-60 cells. The apoptosis and cell cycle changes of the cells in response to apatinib treatment were analyzed by flow cytometry, and Western blotting was used to assay P-Akt and P-Erk1/2 expressions in the cells.
RESULTSApatinib significantly inhibited the proliferation of HL-60 cells in vitro with an IC(50) of 4.96∓0.32 µmol/L. Apatinib treatment significantly increased the apoptotic rate of the cells in a dose-dependent manner, but produced no significant effect on the cell cycle (P>0.05). Western blotting showed that the expressions of P-Akt and P-Erk1/2 decreased in HL-60 cells after a 48-h apatinib treatment.
CONCLUSIONApatinib inhibits the proliferation of HL-60 cells by inducing cell apoptosis probably through the mechanism of inhibiting the expressions of the Akt/Erk1/2 signal transduction pathway.
Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; HL-60 Cells ; Humans ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyridines ; chemistry ; pharmacology
9.Using distance comparison method to build pharmacophore model of epidermal growth factor receptor inhibitors.
Yan-shen GUO ; Feng-ming CHU ; Zong-ru GUO
Acta Academiae Medicinae Sinicae 2004;26(4):379-384
OBJECTIVETo build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors.
METHODSThirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method.
RESULTSValidation of the 3D-pharmacophore model was carried out and novel structures with potential inhibitory activity were selected by means of 3D-searching and docking method.
CONCLUSIONThis method can improve hit rate of lead compounds discovery and can be used to design novel EGFR inhibitors.
Drug Design ; Enzyme Inhibitors ; Epidermal Growth Factor ; metabolism ; Models, Chemical ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; chemistry ; pharmacology ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; chemistry ; Structure-Activity Relationship