2-Methoxyestradiol 2-ME2 improving the synergistic cytotoxic effects of VP16 with VX-680

Osis, preferably in the Leuk Aurka preconcentrated, purified with high expression, but not in normal mononuclear cells or 2-Methoxyestradiol 2-ME2 bone marrow Ren cells of leukemia Chemistry Aurka low myeloma Acute, ‘What a m Window resembled the VX 680 high pharmacological therapeutic response in AML Aurka. In addition Haung et al reported the reduction of phosphorylated AKT 1, caspase activation, cell, and an increase Increase of Bax / Bcl-2-money ratio, a factor known to favor the survival in AML, treatment with SR 680 and improving the synergistic cytotoxic effects of VP16 with VX-680 in AML cells. VX 680 inhibits the phosphorylation of histone H3 at Ser 10, entered Ing a significant reduction in tumor size E in xenograft model of human AML with 75 mg / kg twice t Possible treatment for 13 days.
In pr Clinical models VX 680 blocks the growth of tumor xenografts and induced tumor regression. In the first phase I clinical study was VX 680 as a continuous intravenous infusion over several days for patients who have already been treated with solid tumors. The main dose-limiting toxicity of t was grade 3 neutropenia, with a few nonspecific side effects OSI-930 c-Kit inhibitor such as nausea, fatigue and low grade. Stable disease was observed in a patient with lung cancer and a patient with pancreatic cancer. This inhibitor was phase II clinical trials in patients with myeloid leukemia Mie input Chronic Philadelphia chromosome-positive acute leukemia And chemistry Lymphoma. It should be noted that Merck recently suspended enrollment in clinical trials of the Aurora kinase inhibitor VX 680, up to a comprehensive analysis of all data on the safety of the drug.
The decision was made after vorl Ufigen data on safety, was observed in the QTc Verl EXTENSIONS in a patient based. Patients who are currently enrolled in these studies may continue with VX680 with additional keeping surveillance for QTc Verl EXTENSIONS are treated. MLN8054 MLN8054 is an ATP-competitive inhibitor discovered recently Aurora kinase family, it is very specific but Aurka h Can inactivate here AURKB concentrations. MLN8054 40 times more selective for Aurka AURKB that they are not degraded or regulate the bottom, but inhibits Aurka phosphorylation. MLN8054, at h Higher concentrations, inhibits the phosphorylation of histone H3, an indication of the inhibition AURKB. It induces abnormal mitotic spindles, G2 / M accumulation, cell death by apoptosis, and Ph Phenotypes consistent with inhibition Aurka.
Cells treated with MLN8054 develop an abnormal DNA content. These anomalies treatment with MLN8054 pronounced Gter be over time. Unlike the pan Aurora kinases MLN8054 Aurka more specific reason of their R Is ability to inhibit the phosphorylation of T288, growing the cells into mitosis in vivo. We recently reported the induction of TAp73 protein and various pro-apoptotic gene, PUMA, NOXA and p21 in cells that MLN8054 by various types of p53-deficient tumors. p53-deficient cells are resistant to chemotherapy. This observation that MLN8054 induced TAp73 k nnte To be advantageous in targeting tumors without p53. MLN8237 MLN8237 is an inhibitor of the second generation and has recently joined Aurka Phase I / II clinical trials. It inhibits Aurora A with an IC50 of 1 nM in biochemical assays and has 200 times the selectivity of t for more Aurka AURKAB in cellular Ren assays. A wide-receptors and ion channels Le showed no significant