CN112843055B - Pharmaceutical composition and application thereof in preparation of medicines for treating myeloproliferative diseases of targeted calreticulin mutation type - Google Patents

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

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CN112843055B
CN112843055B CN202110052755.6A CN202110052755A CN112843055B CN 112843055 B CN112843055 B CN 112843055B CN 202110052755 A CN202110052755 A CN 202110052755A CN 112843055 B CN112843055 B CN 112843055B
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marimo
pharmaceutical composition
akt
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CN112843055A (en
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付春玲
胡雪婷
王淑瑾
于翔茹
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Xuzhou Medical University
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention discloses a pharmaceutical composition and application thereof in preparing a medicine for treating a bone marrow proliferative disease of a targeted calreticulin mutation type, wherein the pharmaceutical composition consists of MK-2206and AZD 6244.

Description

Pharmaceutical composition and application thereof in preparation of medicines for treating myeloproliferative diseases of targeted calreticulin mutation type
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a pharmaceutical composition and application thereof in preparing a medicine for treating myeloproliferative diseases of a targeted calreticulin mutation type.
Background
Myeloproliferative Neoplasms (MPNs) are a group of malignant clonal diseases derived from hematopoietic stem cells, and are characterized by hyperproliferation of one or more myeloid cell lines and increased peripheral blood leukocyte and erythrocyte counts, but relatively normal cell morphology, usually accompanied by liver, spleen and lymph node swelling. The disease can be classified into Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) according to its clinical manifestations. The existing research shows that the excessive activation of JAK-STATs signal pathways by mutation of driving genes such as Janus kinase 2(JAK2), thrombopoietin receptor (MPL) and Calreticulin (CALR) is an important factor for MPN attack.
Although MPN is a relatively inert disease, the disease causes splenomegaly, thrombosis, bleeding and 5-20% of PMF patients are at risk of conversion to leukemia and are not curable. At present, the luccotinib has obvious curative effects on improving the general symptoms of patients, reducing the size of spleen, reducing cytokine storm and the like. The application of the JAK2 inhibitor luctinib, which can only relieve symptoms and still cannot eradicate mutant cells, causes relapse in part of patients, and still part of patients have luctinib ineffective against it, which may be a JAK-STATs independent activation mechanism.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
As one aspect of the present invention, the present invention provides a pharmaceutical composition, wherein: the pharmaceutical composition consists of MK-2206and AZD 6244.
Preferably, said composition can be used for the treatment of myeloproliferative diseases of the calreticulin mutant type, including polycythemia vera, essential thrombocythemia, essential myelofibrosis.
Preferably, the molar ratio of MK-2206 to AZD 6244 is 3-4: 1.
preferably, the molar ratio of MK-2206 to AZD 6244 is 3.3-3.7: 1.
as another aspect of the invention, the invention provides the application of the pharmaceutical composition in preparing a medicament for treating myeloproliferative diseases of targeted calreticulin mutation types.
The invention has the beneficial effects that: the MARMO cell of the CALR gene mutation type is used as a research object (the cell is a specific RCAT nonresponsive cell), a double-drug combination method which can be applied to the bone marrow proliferative diseases of the targeted CALR mutation type is explored, and a basis is provided for clinical drug combination treatment of patients who do not respond to RCAT.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein:
FIG. 1 is a graph showing the 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; FIG. 1A is a graph showing the results of measuring the levels of AKT and P-AKT in other myeloid cells of JAK2V617F mutant cell lines (HEL and SET2), CML (K562) patients, and FIG. 1B is a graph showing the results of AKT inhibitor MK-2206 inhibiting CALR mutated MARIMO, JAK2V617F mutant cell line (HEL) cell growth.
FIG. 2 is a graph showing the results of comparative analyses of the expression levels of AKT and P-AKT after the treatment of SET and MARIMO cells with the AKT inhibitor MK-2206and the JAK2 inhibitor incrustinib (RUX), respectively. FIG. 2A is a graph of the effect of MK-2206 alone on the expression levels of AKT and P-AKT in SET and MARIMO cells, and grey value analysis. FIG. 2B is a graph of the effect of RUX alone on the expression levels of AKT and P-AKT in SET and MARIMO cells, and grey value analysis.
FIG. 3 is a graph showing the results of AKT inhibitor MK-2206 inducing cell cycle arrest in CALR mutated MARIMO cells. FIG. 3A is a graph showing the flow results of MK-2206 on MARIMO cells, the cell cycle distribution. FIG. 3B is a statistical analysis of the flow results of MK-2206 on MARIMO cells. FIG. 3C shows the levels of intracellular cyclin changes and statistical analysis after MK-2206 was exposed to MARIMO cells.
FIG. 4 is a graph showing the results of AKT inhibitor MK-2206 inducing apoptosis in CALR mutated MARIMO cells. FIG. 4A is a flow chart showing apoptosis of MK-2206 after it acts on MARIMO cells. FIG. 4B is a statistical plot of apoptosis of MK-2206 after acting on MARIMO cells. FIG. 4C shows the expression level of apoptosis-related protein in cells after MK-2206 acts on MARIMO cells.
FIG. 5 is a graph showing the results of MK-2206and AZD 6244 acting on the half inhibitory concentration (IC50) of CALR mutated MARIMO cells, respectively. FIG. 5A shows IC50 of MK-2206 acting on MARIMO cells. FIG. 5B shows the IC50 of AZD 6244 on MARIMO cells. FIG. 5C shows IC50 for MK-2206 in combination with AZD 6244 on MARIMO cells.
FIG. 6 is a graph showing the results of the synergistic effect of MK-2206and AZD 6244 on CALR mutated MARIMO cells.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The materials used in the invention:
cell: MARIMO cells. MARIMO cells derived from a 68 year old female with a prior history of AML-M2 and ET, and JAK2V617F and MPL mutation negative, carrying a heterozygous CALR61-basepair (bp) deletion, like other types of CALR mutations, the mutation results in a +1-bp shift, giving rise to a new C-terminus. Different from JAK2 and MPL gene mutant cells, MARIMO cells carry CALR gene mutation but have no response to the incarnib, and are used for researching JAK-STATs independent activation mechanism in the subject.
The experimental method comprises the following steps:
western blot analysis of actionable targets in MARIMO cells: cells were plated at 2X 10 per well6Individual cells were grown in 6-well plates and treated with different doses of inhibitor for 24 hours. Cellular proteins were separated on a 10% SDS gel and transferred to nitrocellulose blotting membranes, which were incubated with an antibody and then with an antibody. Reaction proteins were detected using ECL substrate and visualized by ImageQuant LAS 4000. All antibodies were raised at 1: dilution at a ratio of 1000. Immunoblotting was quantified using Image J1.47V.
Apoptosis assay MARIMO cell sensitivity to inhibitors: MARIMO cells were plated at 0.1X 10 per well6Cells were plated in 24-well plates and incubated for Annexin V-PE to detect apoptosis 48 hours after treatment with different doses of MK-2206. Data were collected on a flow cytometer and analyzed using flowjo7.6.1 software.
Cell proliferation assay sensitivity of MARIMO cells to inhibitors: MARIMO cells were treated with the inhibitor for 48 hours, then incubated with EdU at 37 ℃ for 2 hours, and then fixed and permeabilized. Then, the cells were stained with 500 μ LClick-it Plus reaction mixture for 30 minutes at room temperature and the nucleic acids were labeled with DAPI. All data acquisitions were performed on a flow cytometer and analyzed using FlowJo7.6.1 software.
Analysis of the synergistic effect of MK-2206and AZD 6244 on MAROMO cells: MARIMO and SET2 cells at 0.3X 10 per well6Cells were plated in 24-well plates and treated with different doses of AZD 6244 and/or MK-2206, respectively, for 48 hours. IC50 was calculated using GraphPad Prism 6 software. Five single or combined doses of inhibitor were designed to treat cells near IC50 values. Cells were counted using the median effect principle of Chou and talalay (calcusyn software) to calculate Combination Index (CI).
The above experimental methods are applicable to the following examples.
Example 1:
referring to FIG. 1, MARIMO cells, JAK2V617F mutant cell line (HEL and SET2), other myeloid cells of CML (K562) patients were tested for AKT and P-AKT levels, phosphorylated AKT levels were significantly higher in MARIMO cells, whereas phosphorylated AKT levels in HEL and K562 cells were nearly 1.5-fold higher and more than 5-fold higher in SET2 cells (FIG. 1A). 10 μ M MK-2206 exerts a growth inhibitory effect of more than 50% in MARIMO cells. The same treatment with 20 μ M Rux did not reduce the survival of MARIMO cells while SET2 cells were completely killed at 10 μ M Rux (FIGS. 1B and C). The result shows that AKT is activated in MARIMO cells, and the AKT inhibitor can generate inhibition effect on the growth of MARIMO. The JAK2 inhibitor does not affect the growth of MARIMO cells, but has obvious inhibition effect on SET2 cells.
Example 2:
referring to FIG. 2, after treating SET2 and MARIMO cells with 0. mu.M, 1. mu.M, 3. mu.M, 10. mu.M MK-2206and JAK2 inhibitors, respectively, of RuRux, the expression levels of AKT and P-AKT after treatment were measured using Western blot. Western blot detection results show that MK-2206 can obviously reduce the level of P-AKT in MARIMO cells, and the expression of P-AKT in MARIMO cells is not obviously changed after Rux treatment (figure 2A and B). Indicating that MARIMO cells are dependent on AKT and not on the JAK-STAT signaling pathway.
Example 3:
referring to FIG. 3, MARIMO cells were treated with 0. mu.M, 1. mu.M, 3. mu.M, 10. mu.M MK-2206, respectively, for 48 hours, stained with EDU-Alexa Fluor647-A and DAPI flow antibody, and the cell cycle was examined. The expression levels of cyclin D and cyclin E after the treatment are detected by Western blot. Flow cytometry analysis statistics showed that cells in phase-G1 treated with 1 to 10. mu. MMK-2206 were significantly arrested and the proportion of S phase cells labeled with EdU was reduced from the control by-41%, -39.5% and-36% in MARIMO cells (FIGS. 3A and B). The expression of cyclinD and cyclinE is also reduced obviously after MMK-2206 treatment, and Western blot quantification also shows that the down regulation of cyclinD and cyclinE is dose-dependent. Indicating that inhibition of AKT can induce MARIMO cell cycle arrest.
Example 4:
referring to FIG. 4, MARIMO cells were treated with 0. mu.M, 1. mu.M, 3. mu.M, 10. mu.M MK-2206, respectively, for 48 hours, stained with Annexin V-PE flow antibody, and examined for apoptosis. Expression levels of Bcl-2, Bax, caspase-3 were examined by Western blot after the above treatments. Flow cytometry analysis statistics showed that MARIMO cells were sensitive to AKT inhibitors and exhibited apoptosis in a dose-dependent manner. The treatment with 1 mu M MK-2206 can obviously improve the apoptosis rate of MARIMO cells from 5 percent to 12 percent, and further improve the apoptosis rate of MK-2206 with high dose to 36 percent or even 42 percent. (FIGS. 4A, B) Bcl-2 expression was reduced in MARIMO cells after MK-2006 treatment, while cleaved caspase-3 and Bax expression was significantly increased (FIG. 4C). Indicating that MK-2206 can induce the apoptosis of cells MARIMO.
Example 5:
referring to FIG. 5, cell counts were performed 48 hours after treating MARIMO cells with different concentrations of MK-2206and AZD 6244, respectively. For MARIMO cells, the IC50 values for MK-2206and AZD 6244 were 6.6 and 1.98. mu.M (FIGS. 5A and B). The combination of these two drugs significantly inhibited the growth of MARIMO cells (fig. 5C). Indicating that MK-2206and AZD 6244 can inhibit the growth of MARIMO cells.
Example 6:
referring to FIG. 6, Fa and CI values were calculated using the median effect principle of Chou and Talalay based on cell viability after treatment with inhibitors alone or in combination. The calculated CI for each of the five drug combinations was less than 1, indicating a strong synergistic activity between MK-2206and AZD 6244 in the MARIMO cell line (FIG. 6).
The MARMO cell of the CALR gene mutation type is used as a research object (the cell is a specific RCAT nonresponsive cell), a double-drug combination method which can be applied to the bone marrow proliferative diseases of the targeted CALR mutation type is explored, and a basis is provided for clinical drug combination treatment of patients who do not respond to RCAT.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.

Claims (2)

1. An application of a pharmaceutical composition in preparing a medicine for treating myeloproliferative diseases of targeted JAK-STATs independent calreticulin mutation types is characterized in that: the pharmaceutical composition consists of MK-2206and AZD 6244, wherein the molar ratio of the MK-2206 to the AZD 6244 is 3.3-3.7: 1.
2. use according to claim 1, characterized in that: the myeloproliferative diseases comprise polycythemia vera, essential thrombocythemia and essential myelofibrosis.
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CN113549597B (en) * 2021-07-22 2022-03-25 浙江大学 Human primary myelofibrosis cell strain and application thereof
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Title
AKT activation is a feature of CALR mutant Myeloproliferative Neoplasms;Chunling Fu et al.;《Leukemia》;20191231;第33卷(第1期);第271-274页 *
Anthony W. Tolcher et al..Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK.《Clin Cancer Res》.2015,第21卷(第4期),第739-748页. *
Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK;Anthony W. Tolcher et al.;《Clin Cancer Res》;20150215;第21卷(第4期);第739-748页 *
骨髓纤维化患者RAS基因突变特征及其预后意义;吴君颖等;《中华血液学杂志》;20201231;第41卷(第12期);第989-995页 *

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