The resistence to Imatinib is the most problem to the treatment of CML. By a deep research of the drug-resistant mechanism, the second generation tyrosine kinase inhibitor represented by Dasatinib and Nilotinib is applied in clinical treatment of CML resistant to Imatinib. Dasatinib and Nilotinib both bind a ATP-binding site(p-loop) in BCR-ABL competitively with ATP to play a pharmacology effect. BCR-ABL is a fusion protein in a dynamic structure between active and inactive conformations. A Crystal structure research shows that Imatinib and Nilotinib combind with p-lood of ABl only when ABL is in a inactive conformation and active-loop is closed. This special requirement to ABL’s conformation will obviously influence the combination when a mutation occurs. Similar to other tyrosine kinase, Dasatinib can also compete with ATP for the ATP-binding site in certain RTKs. Dasatinib can combind with ABL in lots of comformations. The requirment of this combination for comformation is not as stringent as Imatinib and Nilotinib. It can bind bcr-abl in an active comformation, avoiding the p-loop. Research has proved the mutation of P-loop is the most important style of the resistence to Imatinib, so this characteristic make Dasatinib overcome the resistence to Imatinib and Nilotinib. Moreover, as a multiple target tyrosine kinase inhibitor, Dasatinib can also suppress the activity of SRC family kinase. The members of SRC family kinase, such as arc, lyn and hck are unregulated by bcr-abl to promote cell growth and differentiation. About 30 to 50 percent of resistence to Imatinib is involved in the decompensated activation of SRC kinase pathway. So the advantage of Dasatinib in structure and dual inhibition of abl/src make it more effective to block abl pathway. HIF-1 upregulates several genes to promote survival in hypoxia. These include glycolysis enzymes, which allow ATP synthesis in an oxygen-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIF-1 acts by binding to HIF-responsive elements (HREs) in promoters that contain the sequence NCGTG. HIF-1 stabilization is also found in non-hypoxic conditions through an, until recently, unknown mechanism. It was shown that NF-B (nuclear factor B) is a direct modulator of HIF-1 expression in the presence of normal oxygen pressure. HIF activity is involved in angiogenesis required for cancer tumor growth, so HIF inhibitors are under investigation for anti-cancer effects. VEGF coexists with anti-VEGF evenly in nomal tissue. The balance between VEGF and anti-VEGF regulates the generation and differentiation of the vessel. There are a certain amount of receptors of VEGF called VEGFR located on the surface of human vascular endothelial cells.When VEGF in the blood binds VEGFR, it activates the intracellular tyrosine kinase and initiates downstream signaling pathway. As a result, it stimulates the form of new vessel. When VEGF is secreted from tumor cells, it interacts with cell-surface receptors, including VEGFR-1 and -2, located on vascular endothelial cells and bone-marrow derived cells. VEGFR-2 is believed to mediate the majority of the angiogenic effects of VEGF-A while the role of VEGFR-1 is complex and not fully understood. A soluble form of VEGFR-1 can act as a decoy receptor, preventing VEGF-A from acting on VEGFR-2 and activating signaling pathways. However, there is also evidence that indicates VEGFR-1 plays an important role in developmental angiogenesis. A third receptor, VEGFR-3, is involved in lymphangiogenesis and does not bind VEGF-A. Related posts: Src Family Kinases Dual Src/Abl kinase Inhibitor Reference: Dasatinib
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