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Application of LY3009120 in preparation of medicine for treating myeloproliferative tumors

A bone marrow proliferation and drug technology, applied in the field of medicine, can solve the problems of narrow scope, inability to fundamentally treat myeloproliferative tumors, high cost of bone marrow transplantation, etc., and achieve the effect of low cost and good clinical application prospects

Active Publication Date: 2021-07-09
THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Bone marrow transplantation is expensive and, in the current medical environment, not an option for most patients
[0004]Although ruxolitinib is a milestone drug in the treatment of myeloproliferative neoplasms, the scope of application of ruxolitinib is currently narrow, and bone marrow suppression is a common side effect limitation Its application in the main indication MF
Ruxolitinib cannot reduce the burden of mutant genes, which means that ruxolitinib treatment cannot achieve molecular remission of the disease and cannot fundamentally treat myeloproliferative neoplasms
Especially after the emergence of ruxolitinib resistance, limited treatment drugs are currently a major challenge

Method used

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  • Application of LY3009120 in preparation of medicine for treating myeloproliferative tumors
  • Application of LY3009120 in preparation of medicine for treating myeloproliferative tumors
  • Application of LY3009120 in preparation of medicine for treating myeloproliferative tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1, the establishment of two common ruxolitinib drug-resistant cell models (HEL RE , SET2 RE ).

[0048] 1. Materials and methods

[0049] 1. Cell line

[0050] HEL (Human erythroleukemia cell line), ruxolitinib-resistant HEL cells, SET2 cells and ruxolitinib-resistant SET2 cells were all cultured in 20% heat-inactivated fetal bovine serum (Gibco) and 1% penicillin / Streptomycin in RPMI medium (Gibco).

[0051] HEL model of ruxolitinib resistance RE The model was constructed by starting to add ruxolitinib at a concentration lower than the IC50 of the original cells, and slowly increasing to a high concentration to maintain the cells from being killed. Our initial concentration was 0.1 μM, and the drug was added as soon as the cells proliferated, and the drug addition gradient was 1.25 times increasing, and the final concentration was 2.0 μM. Stable drug-resistant cells were obtained after 4-6 weeks. Another ruxolitinib resistance model is SET2 RE That ...

Embodiment 2

[0060] Example 2, LY3009120 can inhibit the proliferation of myeloproliferative tumor cells

[0061] In order to detect the effect of LY3009120 on the proliferation of drug-resistant cells in myeloproliferative neoplasms, the method was to use increasing concentrations of ruxolitinib and LY3009120 to treat HEL primitive cell lines and SET2 primitive cell lines respectively, and use CellTiter-Lumi TM Luminescence method is used to detect the proliferation of cells, the method is the same as in Example 1, and the results are shown in figure 2 .

[0062] figure 2 a reflects that in HEL cells, the ruxolitinib treatment group drug concentration (average proliferation rate % ± standard deviation) is: 0 μ M (100 ± 2.40) (not shown in the figure), 0.1 μ M (77.9 ± 2.43), 1 μ M ( 43.2±3.75), 2.5μM (50.6±2.19), 5μM (47.0±1.15); LY3009120 treatment group drug concentration (average proliferation rate) was: 0μM (100±7.65) (not shown in the figure), 0.1μM (61.7± 5.66), 1 μM (39.5±1.39)...

Embodiment 3

[0063]Example 3, LY3009120 can promote the apoptosis of myeloproliferative tumor cells

[0064] 1. Materials and methods

[0065] 1. Cell lines and inhibitors are the same as in Example 1.

[0066] 2. Apoptosis detection

[0067] In order to detect the pro-apoptotic effect of inhibitors, ruxolitinib and LY3009120 were used to treat HEL primitive cell lines and SET2 primitive cell lines for 24 hours (concentration: 0, 0.1, 0.5, 1 μM), and supplemented with DMSO to the same amount. Three parallel repeat groups were set up, and the apoptosis of cells was detected by flow cytometry after AnnexinV and PI staining.

[0068] Apoptosis rate calculation formula: cell apoptosis rate = early apoptotic cell ratio (AnnexinV + / PI - )+ ratio of late apoptotic cells and necrotic cells (AnnexinV + / PI + ).

[0069] 2. Results Analysis

[0070] image 3 In a, the drug concentration (average apoptosis rate%±standard deviation) of the HEL cell ruxolitinib treatment group was: 0 μM (4.37...

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Abstract

The invention relates to the technical field of medicines, in particular to application of LY3009120 in preparation of a medicine for treating myeloproliferative tumors. The myeloproliferative tumors comprise polycythemia vera, primary thrombocythemia and myelofibrosis, and particularly, the myeloproliferative tumors resistant to rucotinib. When the LY3009120 is used for treating the myeloproliferative tumors, a new treatment way is provided for the majority of patients with the myeloproliferative tumors, and more choices are provided for clinicians and the patients. For a myeloproliferative tumor patient with drug resistance to rucotinib, LY3009120 can provide continuous oral drug treatment for the patient, and bone marrow transplantation is avoided. LY3009120 can be chemically synthesized, and the cost is lower than that of a biological agent. And through a first-stage clinical experiment, the side reaction is less and lighter, and the tolerance of a clinical patient is good.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the application of LY3009120 in the preparation of medicines for treating myeloproliferative tumors. Background technique [0002] Myeloproliferative neoplasms (MPNs) refer to a group of neoplastic diseases caused by the clonal proliferation of one or more lines of myeloid cells with relatively mature differentiation. Clinically, one or more blood cell proliferations are accompanied by enlargement of the liver, spleen, or lymph nodes. In 2016, the World Health Organization (WHO) revised the classification of bone marrow tumors, and classified polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (essential thrombocythemia, ET) is included in the category of Philadelphia-negative classical myeloproliferative neoplasms. Myeloproliferative neoplasms are clonal hematopoietic stem cell diseases. The main disease-driving gene mutations include JAK2 / V617F...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P35/00A61P35/04
CPCA61K31/519A61P35/00A61P35/04
Inventor 邓沱胡婉钰吾甫尔
Owner THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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