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Pharmaceutical composition and application thereof in preparation of drugs for treating targeted calreticulin mutation type myeloproliferative diseases

A technology for bone marrow proliferation and calreticulin, applied in the field of biomedicine, can solve the problems of patient recurrence and inability to eradicate mutant cells.

Active Publication Date: 2021-05-28
XUZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The application of JAK2 inhibitor ruxolitinib can only relieve the symptoms but still cannot eradicate the mutant cells, causing some patients to relapse, and there are still some patients who are ineffective to ruxolitinib. Patients who are ineffective to ruxolitinib may be JAK-STATs independent activation mechanism

Method used

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  • Pharmaceutical composition and application thereof in preparation of drugs for treating targeted calreticulin mutation type myeloproliferative diseases
  • Pharmaceutical composition and application thereof in preparation of drugs for treating targeted calreticulin mutation type myeloproliferative diseases
  • Pharmaceutical composition and application thereof in preparation of drugs for treating targeted calreticulin mutation type myeloproliferative diseases

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Effect test

Embodiment 1

[0030] Reference attached figure 1 , detection of AKT and P-AKT levels in MARIMO cells, JAK2V617F mutant cell lines (HEL and SET2), and other myeloid cells of CML (K562) patients, the levels of phosphorylated AKT in MARIMO cells were significantly higher, while HEL and K562 Phosphorylated AKT levels were nearly 1.5-fold higher in cells and more than 5-fold higher in SET 2 cells ( figure 1 A). 10 μM MK-2206 exerted more than 50% growth inhibitory effect in MARIMO cells. The same treatment with 20 μM Rux did not reduce the survival of MARIMO cells while SET 2 cells were completely killed at 10 μM Rux ( figure 1 B and C). It shows that AKT is activated in MARIMO cells, and AKT inhibitors can inhibit the growth of MARIMO. JAK2 inhibitors did not affect the growth of MARIMO cells, but had a significant inhibitory effect on SET2 cells.

Embodiment 2

[0032] Reference attached figure 2 , after treating SET2 and MARIMO cells with 0μM, 1μM, 3μM, 10μM MK-2206 and JAK2 inhibitor Rux, respectively, the expression levels of AKT and P-AKT were detected by Western blot. The results of Western blot showed that MK-2206 could significantly reduce the level of P-AKT in MARIMO cells, and the expression of P-AKT in MARIMO cells did not change significantly after Rux treatment ( figure 2 A and B). It shows that MARIMO cells depend on AKT but not on JAK-STAT signaling pathway.

Embodiment 3

[0034] Reference attached image 3 , MARIMO cells were treated with 0 μM, 1 μM, 3 μM, and 10 μM MK-2206 for 48 hours, stained with EDU-Alexa Fluor647-A and DAPI flow cytometry antibodies, and detected the cell cycle. After the above treatment, the expression levels of CyclinD and CyclinE were detected by Western blot. The statistical results of flow cytometry showed that compared with the control group, cells in -G1 phase treated with 1 to 10 μM K-2206 were significantly arrested, and the proportion of cells in S phase labeled with EdU decreased from the control percentage in MARIMO cells are ~41%, ~39.5% and ~36% ( image 3 A and B). The expressions of CyclinD and CyclinE were also significantly decreased after MMK-2206 treatment, and Western blot quantification also showed that the down-regulation of CyclinD and CyclinE in the cell cycle was dose-dependent. It shows that AKT inhibition can induce MARIMO cell cycle arrest.

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Abstract

The invention discloses a pharmaceutical composition and an application thereof in preparation of drugs for treating targeted calreticulin mutation type myeloproliferative diseases, wherein the pharmaceutical composition is composed of MK-2206 and AZD 6244; CALR gene mutation type MARMO cells are adopted as research objects (the cells are specific unresponsive cells of rucotinib), a double-drug combination method capable of being applied to targeted CALR mutation type myeloproliferative diseases is explored, and a basis is provided for clinical drug combination treatment of patients who do not respond to rucotinib.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a pharmaceutical composition and its application in the preparation of drugs for treating myeloproliferative diseases targeting calreticulin mutation types. Background technique [0002] Myeloproliferative neoplasms (Myeloproliferative Neoplasms, MPNs) are a group of malignant clonal diseases originating from hematopoietic stem cells, which are specifically manifested as hyperplasia of one or more lines of myeloid cells and increased counts of white blood cells and red blood cells in peripheral blood, but the cell morphology is relatively normal. Usually accompanied by liver, spleen and lymphadenopathy. According to different clinical manifestations, the disease can be divided into polycythemia vera (PV), essential thrombocythemia (Essential Thrombocythemia, ET) and primary myelofibrosis (Primary Myelofibrosis, PMF). Existing studies have shown that driver gene mu...

Claims

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Application Information

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IPC IPC(8): A61K31/4375A61K31/4184A61P7/00A61P35/00
CPCA61K31/4375A61K31/4184A61P7/00A61P35/00A61K2300/00
Inventor 付春玲胡雪婷王淑瑾于翔茹
Owner XUZHOU MEDICAL UNIV
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