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Novel purpose of A674563 in acute leukemia carrying FLT3 mutation genes

A kind of FLT3-D835Y, mutant technology, applied in the field of medicine

Active Publication Date: 2017-01-04
HEFEI INSTITUTES OF PHYSICAL SCIENCE - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no relevant report on the use of A674563 in the treatment of acute myeloid leukemia carrying the FLT3 mutant gene, and there is no report on the use of A674563 in the treatment of patients with FLT3 mutant gene carrying drug resistance associated with high expression of FL ligands Related reports of patients with acute myeloid leukemia

Method used

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  • Novel purpose of A674563 in acute leukemia carrying FLT3 mutation genes
  • Novel purpose of A674563 in acute leukemia carrying FLT3 mutation genes
  • Novel purpose of A674563 in acute leukemia carrying FLT3 mutation genes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Effect of A674563 on proliferation of cancer cells

[0046] The selectivity of A674563 to inhibit the proliferation of cancer cells was evaluated by testing the effect of A674563 on the growth of cancer cells.

[0047] In this embodiment, acute myeloid leukemia cells HL-60 (expressing wild-type FLT3 gene), acute promyelocytic leukemia cell line NB-4 (Lu+) (expressing wild-type FLT3 gene), human acute myeloid leukemia cells OCI-AML-3 (expressing FLT3 A680V mutant gene), human acute myeloid leukemia cell line MOLM-14 (expressing FLT3-ITD mutant gene and wild-type FLT3 gene), human acute myeloid leukemia cell line MOLM-13 (express FLT3-ITD mutant gene and wild-type FLT3 gene), human acute myeloid leukemia cell line MV-4-11 (express FLT3-ITD mutant gene), MDS-RAEB (myelodysplastic syndrome-increased blast type) cell line SKM-1 (expressing wild-type FLT3 gene), human acute myeloid leukemia cell line U-937 (expressing wild-type FLT3 gene), mouse cell BaF3. The ...

Embodiment 2

[0060] Example 2: Effects of A674563 on Upstream and Downstream Signaling Pathways in Cells

[0061] In human acute myeloid leukemia cell line MV-4-11 (expressing FLT3-ITD mutant gene), human acute myeloid leukemia cell line MOLM-13 (expressing FLT3-ITD mutant gene and wild-type FLT3 gene) and human In the acute myeloid leukemia cell line MOLM-14 (expressing FLT3-ITD mutant gene and wild-type FLT3 gene), the effects of A674563 on FLT3 protein kinase, PKB / AKT kinase and the phosphorylation of STAT5, ErK, GSK3β, FOX01, PRAS40, p70S6K, and 4EBP1 proteins closely related to FLT3 kinase and PKB / AKT kinase. At the same time, we also detected the effect of A674563 on the phosphorylation of protein C-Myc and transcription factor NF-κB subunit p65 ( figure 1 a). With different concentrations of 0 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM (in DMSO) of A674563 and 1 μM (in DMSO) of PKB / AKT inhibitor GSK690693, PKB / AKT inhibitor MK2206, FLT3 inhibitor TCS359 Treat MOLM-13, MOLM-14, MV...

Embodiment 3

[0065] Example 3: FLT3 autophosphorylation in the BaF3 cell line of the A674563 equivalent locus Effects of Acidification

[0066] Mouse TEL-FLT3-BaF3 (activated kinase stably expressing wild-type FLT3) cells, mouse BaF3-FLT3-ITD (activating kinase stably expressing FLT3 ITD mutation) cells, mouse BaF3-FLT3-D835Y (stably expressing FLT3 D835Y mutant activated kinase) cells, mouse BaF3-FLT3-ITD-D835Y (stable expression of FLT3-ITD+D835Y mutant activated kinase) cells, mouse BaF3-FLT3-ITD-F691L (stable expression of FLT3-ITD+F691L mutant activated kinase) cells (see Example 1 for the construction method of these cells). The effect of A674563 on the autophosphorylation of FLT3 and / or FLT3-ITD mutant protein kinases in cells was tested in the above cell lines ( figure 2 ). Treated with different concentrations of 0 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM (in DMSO) of A674563, 0.05 μM (in DMSO) of FLT3 kinase inhibitor AC220 (purchased from Hao YuanChemexpress Company (Shang...

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Abstract

The invention relates to a novel purpose of A674563 in preparation of medicine for treating a patient with acute myelocytic leukemia carrying FLT3 mutation genes, wherein the patient with the leukemia can have or cannot have the drug resistance associated with high expression of FL ligands. The invention also relates to a method of inhibiting acute myelocytic leukemia cells carrying FLT3 mutation genes in a non-treatment goal. The method comprises the step of contacting the cells with the A674563.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a new application of A-674563 (A674563). Background technique [0002] Acute myelocytic leukemia (AML) or acute nonlymphocytic leukemia (ANLL) includes all acute leukemias of non-lymphocyte origin. It is a kind of disease formed by the karyotype mutation of pluripotent stem cells or slightly differentiated precursor cells, and it is a clonal malignant disease of the hematopoietic system. Epidemiological surveys show that environmental, occupational and genetic factors are closely related to the pathogenesis of AML. The incidence rate is higher in developed countries than in developing countries, and higher in western countries than in eastern countries. The annual incidence rate around the world is 2.25 / 100,000 population, and the incidence rate increases with age. It begins to rise significantly at the age of 50, reaches a peak at the age of 60-69, and the incidence rate is 1 / 100,000 u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61P35/02
CPCA61K31/136
Inventor 刘青松刘静王傲莉吴宏陈程胡晨王文超刘晓川余凯琳赵铮吴佳昕刘娟王黎王蓓蕾
Owner HEFEI INSTITUTES OF PHYSICAL SCIENCE - CHINESE ACAD OF SCI