CN111068055A - Combined inhibitor and application thereof - Google Patents
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Abstract
A combination inhibitor comprising a histone deacetylase 8 specific inhibitor and an FLT3 inhibitor. By utilizing the specific inhibitor of the histone deacetylase 8, the resistance mechanism that the leukemia cells up-regulate the expression of the histone deacetylase 8 and resist the FLT3 inhibitor is eliminated, so that the FLT3-ITD positive acute myelogenous leukemia is more effectively treated.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a combined inhibitor and application thereof in medicaments for treating acute myeloid leukemia, especially FLT3-ITD mutation positive acute myeloid leukemia.
Background
The FLT3-ITD mutation is one of the most common mutations in acute myeloid leukemia, and about 25-30% of leukemia cells of patients with acute myeloid leukemia contain FLT3-ITD mutant.
The FLT3-ITD mutation can cause activation of a series of downstream cell pathways promoting survival and proliferation of leukemia cells, so that the acute myelogenous leukemia has high recurrence rate and poor long-term prognosis. Thus, both international guidelines (NCCN and ELN) do not list FLT3-ITD mutation positive as an independent risk factor for poor prognosis of acute myeloid leukemia.
Aiming at FLT3-ITD positive mutation, multiple small and medium molecular targeted inhibitors are developed at present, such as first-generation Sorafenib and PKC412, second-generation Quizartinib and Gilteritinib and the like. These targeted inhibitors are used alone or in combination with chemotherapy to treat acute myeloid leukemia positive for FLT3-ITD mutation.
However, current clinical studies indicate that the effect of FLT3 inhibitors on FLT3-ITD mutation-positive acute myeloid leukemia is not ideal. Although a more rapid response to treatment may occur after the use of the inhibitor, such as complete or partial remission of the leukemia, the disease will relapse rapidly and lose its effectiveness as an inhibitor. Thus, there is a mechanism of resistance to the inhibitor in the FLT3-ITD mutation positive leukemia cells, making the inhibitor unable to exert an anti-leukemic effect.
Therefore, a new therapeutic target needs to be found, the drug resistance of leukemia cells is overcome, and the aim of better treating FLT3-ITD mutation positive acute myeloid leukemia is achieved.
Disclosure of Invention
The invention aims to provide a combined inhibitor which can effectively eliminate the resistance of FLT3-ITD mutation positive leukemia cells to a FLT3 inhibitor and kill the leukemia cells more effectively.
To achieve the above object, according to an aspect of the present invention, a combined inhibitor comprises a histone deacetylase 8 specific inhibitor and an FLT3 inhibitor.
In one embodiment of the invention, the FLT3 inhibitor comprises a compound of formula I:
in one embodiment of the present invention, the specific inhibitor of histone deacetylase 8 is a specific inhibitor 22d of histone deacetylase 8. The histone deacetylase 8 specific inhibitor 22d comprises a compound shown in formula II and pharmaceutically acceptable salts thereof:
according to another aspect of the present invention there is provided an inhibitor of the FLT3-ITD mutant comprising a histone deacetylase 8 specific inhibitor and an FLT3 inhibitor.
According to another aspect of the invention, there is provided the use of a combination inhibitor as described above in the preparation of an inhibitor for synergistically inhibiting the FLT3-ITD mutant.
According to another aspect of the invention there is provided the use of a combination inhibitor as described above or an inhibitor of the FLT3-ITD mutant as described above in the manufacture of a medicament for the treatment of acute myeloid leukaemia.
According to another aspect of the invention, there is provided the use of a combination inhibitor as described above or an inhibitor of the FLT3-ITD mutant as described above in the manufacture of a medicament for the treatment of acute myeloid leukemia positive for the FLT3-ITD mutation.
In the invention, by utilizing the specific inhibitor of histone deacetylase 8, the resistance mechanism that the expression of histone deacetylase 8 is up-regulated by leukemia cells to resist the FLT3 inhibitor is eliminated, so that the FLT3-ITD positive acute myelogenous leukemia is more effectively treated.
Drawings
FIGS. 1A to 1D show the apoptosis and proliferation of FLT3-ITD mutation positive acute myeloid leukemia cell lines MV4-11 and MOLM-13 under the treatment of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22D with different doses and modes.
FIG. 2 shows the apoptosis of FLT3-ITD mutation positive acute myelogenous leukemia patient specimens treated in different ways.
FIG. 3 shows the number of colonies formed by leukemia cells from a specimen from an acute myeloid leukemia patient positive for FLT3-ITD mutation treated in different ways.
FIG. 4 is a survival curve of the differently treated group MV4-11 leukemic mice.
FIG. 5 is a flow chart of a mouse leukemia model constructed from FLT3-ITD mutation positive acute myelogenous leukemia patient specimens and subsequent experimental studies.
FIGS. 6A and 6B are the proportion of human CD45 and CD33 double positive cells in the bone marrow of leukemic mice treated in different ways.
FIGS. 7A and 7B are the proportion and number of human CD45 positive cells in the bone marrow of leukemic mice treated in different ways.
FIG. 8 survival curves of leukemic mice treated in different ways.
Detailed Description
Hereinafter, the technique of the present invention will be described in detail with reference to specific embodiments. It should be understood that the following detailed description is only for the purpose of assisting those skilled in the art in understanding the present invention, and is not intended to limit the present invention.
The inventor discovers through scientific experimental research that: an endogenous mechanism for resisting the FLT3 inhibitor exists in the FLT3-ITD mutation positive acute myeloid leukemia, namely, under the condition of the FLT3 inhibitor treatment, leukemia cells can up-regulate the expression of histone deacetylase 8, and further resist the killing effect of the FLT3 inhibitor on the leukemia cells. The inventors further found that the combined use of histone deacetylase 8 inhibitors can eliminate this resistance mechanism, thereby treating FLT3-ITD mutation-positive acute myeloid leukemia more effectively.
Example 1 FLT3-ITD mutation-positive acute myeloid leukemia cell lines MV4-11 and MOLM-13
In this example, the killing effect of a combined inhibitor of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22d on FLT3-ITD positive acute myeloid leukemia cell lines MV4-11 and MOLM-13 was considered.
In this example, FLT3-ITD positive acute myeloid leukemia cell line MV4-11 and FLT3-ITD positive acute myeloid leukemia cell line MOLM-13 were treated with FLT3 inhibitor AC220 alone as a control group, and FLT3-ITD positive acute myeloid leukemia cell line MV4-11 and FLT3-ITD positive acute myeloid leukemia cell line MOLM-13 with a combined inhibitor of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22D as an experimental group, to obtain the proportion of apoptotic cells and the proliferation of cells at different concentrations, respectively, as shown in FIGS. 1A to 1D.
The inhibitors used were: FLT3 inhibitor AC220 as control group, FLT3 inhibitor AC220 as experimental group and histone deacetylase 8 specific inhibitor 22 d; wherein, the usage amount of the histone deacetylase 8 specific inhibitor 22d is 10 mu mol/L.
The dosage of the inhibitor is as follows: various concentrations (0nmol/L to 10nmol/L) of FLT3 inhibitor AC220 were considered. Thus, in the control group, the concentrations of FLT3 inhibitor AC220 were 0nmol/L, 1nmol/L, 2nmol/L, 5nmol/L, and 10 nmol/L. In the experimental group, the combined inhibitor was prepared by keeping the amount of the histone deacetylase 8 specific inhibitor 22d used at 10. mu. mol/L and combining the inhibitor with the FLT3 inhibitor AC220 at concentrations of 0nmol/L, 1nmol/L, 2nmol/L, 5nmol/L and 10nmol/L, respectively. That is, when the concentration of FLT3 inhibitor AC220 is 0nmol/L, it means that only histone deacetylase 8 specific inhibitor 22d is present in the combined inhibitor.
Firstly, FLT3 inhibitor AC220 with different concentrations (0 nM-10 nM) and combined inhibitor are respectively used for treating FLT3-ITD positive acute myeloid leukemia cell strain MV4-11, wherein, 3 × 105Resuspending the FLT3-ITD positive acute myeloid leukemia cell line MV4-11 cells at a density of/ml. After 24 hours, cells were harvested and the proportion of apoptotic cells was flow-detected using Annexin V/PI staining, obtaining the results shown in FIG. 1A.
As can be seen from FIG. 1A, under the same dosage, the combined inhibitor consisting of the FLT3 inhibitor AC220 and the histone deacetylase 8 specific inhibitor 22d in the experimental group has obviously better killing effect on the FLT3-ITD positive acute myeloid leukemia cell strain MV4-11 than the FLT3 inhibitor AC220 in the control group. Moreover, as can be seen from the data of the experimental groups, the effect of using only the histone deacetylase 8 specific inhibitor 22d is significantly inferior to the combined inhibitor of the histone deacetylase 8 specific inhibitor 22d and the FLT3 inhibitor AC 220.
Secondly, FLT3-ITD positive acute myeloid leukemia cell strain MOLM-13 is treated by FLT3 inhibitor AC220 with different concentrations (0nM to 10nM) and a combined inhibitor consisting of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22d respectively, whereinAt 3X 105Resuspending the FLT3-ITD positive acute myeloid leukemia cell line MOLM-13 cells at a density of/ml. After 24 hours, cells were harvested and the proportion of apoptotic cells was flow-detected using Annexin V/PI staining, obtaining the results shown in fig. 1B. In this example, the concentration of FLT3 inhibitor AC220 at 0nM represents: only histone deacetylase 8 specific inhibitor 22d was included in the combined inhibitors, and FLT3 inhibitor AC220 was not included.
As can be seen from FIG. 1B, under the same dosage, the combined inhibitor consisting of the FLT3 inhibitor AC220 and the histone deacetylase 8 specific inhibitor 22d in the experimental group has obviously better killing effect on the FLT3-ITD positive acute myeloid leukemia cell strain MOLM-13 than the FLT3 inhibitor AC220 in the control group. Moreover, as can be seen from the data of the experimental groups, the effect of using only the histone deacetylase 8 specific inhibitor 22d is significantly inferior to the combined inhibitor of the histone deacetylase 8 specific inhibitor 22d and the FLT3 inhibitor AC 220.
Subsequently, the CCK-8 kit was used to detect the proliferation of MV4-11 cells after treatment with different concentrations (0nM to 10nM) of the FLT3 inhibitor AC 220. The principle of CCK-8 to detect cell survival and proliferation: the CCK-8 reagent contains WST-8, which can be reduced into a highly water-soluble yellow formazan product under the action of cell mitochondrial dehydrogenase. The amount of formazan product generated is directly proportional to the number of viable cells. Then, an enzyme linked immunosorbent assay (ELISA) detector is used for detecting the absorbance value (A) at the wavelength of 450nm, and the number of the living cells can be reflected. Specifically, cells in the logarithmic growth phase were taken and the concentration was adjusted to 3X 10 cells per well4The individual cells were seeded in a 96-well plate in a volume of 100. mu.l. And setting a zero setting hole (only adding 100 mul of culture medium), a control hole (total 100 mul of cells, drug dissolution medium and culture solution) and an adding drug group (FLT3 inhibitor AC220, combined inhibitor consisting of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22 d) with different concentrations, wherein each concentration is provided with 3 multiple holes, and the system of each hole is 100 mul. 200 mul of sterile PBS was added to a blank circle of wells around the experimental wells to prevent evaporation of cell sap during the culture process and interference with the experimental results. The culture was continued at 37 ℃. After 48 hours, 10 mul CCK-8 reagent is added into each hole, the culture is continued for 2 hours, after the complete color development,the absorbance (A) of each well was measured at 450nm using a microplate reader. The results were averaged for each 3 wells and expressed as the cytostatic: growth rate (%) - (sample a-a blank)/(control a-a blank) × 100%. Finally, the results shown in fig. 1C were obtained.
As can be seen from FIG. 1C, the combined inhibitor consisting of the FLT3 inhibitor AC220 and the histone deacetylase 8 specific inhibitor 22d in the experimental group has obviously better killing effect on FLT3-ITD positive acute myeloid leukemia cell strains MV4-11 than the FLT3 inhibitor AC220 in the control group under the same dosage. Moreover, as can be seen from the data of the experimental groups, the effect of using only the histone deacetylase 8 specific inhibitor 22d is significantly inferior to the combined inhibitor of the histone deacetylase 8 specific inhibitor 22d and the FLT3 inhibitor AC 220.
Finally, the cell proliferation of MOLM-13 cells after treatment with different concentrations (0nM to 10nM) of FLT3 inhibitor AC220 was examined using the CCK-8 kit. Cells in logarithmic growth phase were taken and the concentration was adjusted to 3X 10 cells per well4The individual cells were seeded in a 96-well plate in a volume of 100. mu.l. And setting a zero setting hole (only adding 100 mul of culture medium), a control hole (total 100 mul of cells, drug dissolution medium and culture solution) and an adding drug group (FLT3 inhibitor AC220, combined inhibitor consisting of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22 d) with different concentrations, wherein each concentration is provided with 3 multiple holes, and the system of each hole is 100 mul. 200 mul of sterile PBS was added to a blank circle of wells around the experimental wells to prevent evaporation of cell sap during the culture process and interference with the experimental results. The culture was continued at 37 ℃. After 48 hours, 10 mul CCK-8 reagent is added into each hole, the culture is continued for 2 hours, after the complete color development, the absorbance (A) value of each hole is detected by a microplate reader at 450 nm. The results were averaged for each 3 wells and expressed as the cytostatic: growth rate (%) - (sample a-a blank)/(control a-a blank) × 100%. Finally, the results shown in fig. 1D were obtained.
As can be seen from FIG. 1D, under the same dosage, the combined inhibitor consisting of the FLT3 inhibitor AC220 and the histone deacetylase 8 specific inhibitor 22D in the experimental group has obviously better killing effect on the FLT3-ITD positive acute myeloid leukemia cell strain MOLM-13 than the FLT3 inhibitor AC220 in the control group. Moreover, as can be seen from the data of the experimental groups, the effect of using only the histone deacetylase 8 specific inhibitor 22d is significantly inferior to the combined inhibitor of the histone deacetylase 8 specific inhibitor 22d and the FLT3 inhibitor AC 220.
Example 2.
The inhibitors used were: a blank group without inhibitor, a control group 1 with FLT3 inhibitor AC220, a control group 2 with histone deacetylase 8 specific inhibitor 22d, and an experimental group with a combined inhibitor of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22 d.
Inhibitor dosage: the dosage of the FLT3 inhibitor AC220 is 20nmol/L, and the dosage of the histone deacetylase 8 specific inhibitor 22d is 10 mu mol/L
The processing object is as follows: at 1 × 106Resuspend patient specimens at a density of ml.
The method comprises the following steps: the samples treated by each inhibitor group were collected at 24 hours, and the ratio of apoptotic cells was detected by flow-type detection using annexin v/PI staining, and the detection results are shown in fig. 2.
In FIG. 2, two different patient specimens are shown above and below. As can be seen from fig. 2, the use of the combined inhibitor consisting of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22d induced more apoptosis in leukemia cells than the use of FLT3 inhibitor AC220 or histone deacetylase 8 specific inhibitor 22d alone.
Example 3.
In this example, the effect of the combination inhibitors described in the present invention on clonality of FLT3-ITD mutation positive acute myeloid leukemia cells is considered.
The inhibitors used were: a blank group without inhibitor, a control group 1 with FLT3 inhibitor AC220, a control group 2 with histone deacetylase 8 specific inhibitor 22d, and an experimental group with a combined inhibitor of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22 d.
Inhibitor dosage: the dosage of the FLT3 inhibitor AC220 is 20nmol/L, and the dosage of the histone deacetylase 8 specific inhibitor 22d is 10 mu mol/L
The processing object is as follows: CD34 positive cells.
The method comprises the following steps: CD34 positive cells were isolated from FLT3-ITD mutation positive acute myeloid leukemia patient specimens, treated with each group of inhibitors for 24 hours, then resuspended in semisolid medium containing methylcellulose for colony formation assay, and the number of colonies formed was recorded after 14 days to obtain the experimental results shown in fig. 3.
As can be seen from FIG. 3, the simultaneous targeting of FLT3 and histone deacetylase 8 can significantly inhibit the clonogenic capacity of FLT3-ITD mutation-positive acute myeloid leukemia cells. It can be seen that the combined inhibitor consisting of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22d can inhibit the clonogenic capacity of leukemia cells more than the FLT3 inhibitor AC220AC220 or histone deacetylase 8 specific inhibitor 22d alone.
Example 4.
In this example, the effect of the combination inhibitors of the invention on the survival of cells of MV4-11 leukemic mice is considered.
The inhibitors used were: blank with no inhibitor, control 1 with FLT3 inhibitor AC220, control 2 with histone deacetylase 8 specific inhibitor 22d, and a combined inhibitor of FLT3 inhibitor AC220 with histone deacetylase 8 specific inhibitor 22 d.
The administration mode comprises the following steps: control group 1: 10mg/kg/d, and performing intragastric administration; control group 2: 100mg/kg/d, administered intraperitoneally; experimental groups: 10mg/kg/d FLT3 inhibitor AC220 and 100mg/kg/d histone deacetylase 8 specific inhibitor 22d, were administered intraperitoneally.
The processing object is as follows: NOD-SCID immunodeficient mice were used, and after irradiation with gamma rays (250cGy) of a semi-lethal dose, each mouse was transplanted 2X 10 from the tail vein6MV4-11 cells.
The survival time of each group of mice was observed by continuously administering the inhibitor for 2 weeks in the above-described inhibitor and administration method, and the experimental results shown in FIG. 3 were obtained. As shown in fig. 4, targeting FLT3 and histone deacetylase 8 simultaneously significantly prolonged survival in MV4-11 leukemic mice, i.e., survival in MV4-11 leukemic mice was significantly more prolonged using a combination inhibitor consisting of FLT3 inhibitor AC220 and histone deacetylase 8-specific inhibitor 22d than using FLT3 inhibitor AC220 or histone deacetylase 8-specific inhibitor 22d alone.
Example 5.
In this example, the effect of the combination inhibitors described in this invention on survival of FLT3-ITD mutation positive acute myeloid leukemia mice is considered.
The inhibitors used were: blank with no inhibitor, control 1 with FLT3 inhibitor AC220, control 2 with histone deacetylase 8 specific inhibitor 22d, and a combined inhibitor of FLT3 inhibitor AC220 with histone deacetylase 8 specific inhibitor 22 d.
The administration mode comprises the following steps: control group 1: 10mg/kg/d, and performing intragastric administration; control group 2: 100mg/kg/d, administered intraperitoneally; experimental groups: 10mg/kg/d FLT3 inhibitor AC220 and 100mg/kg/d histone deacetylase 8 specific inhibitor 22d, were administered intraperitoneally.
The processing object is as follows: NOD-SCID immunodeficient mice constructed from FLT3-ITD positive acute myeloid leukemia patient specimens were used and the construction is shown in FIG. 5. As shown in FIG. 5, a specimen of FLT 3-ITD-positive acute myeloid leukemia patients was isolated and injected from the tail vein into NOG immunodeficient mice irradiated with semi-lethal gamma radiation (200cGy), 2X 10 per mouse6A cell. The mice were tested for the onset of leukemia, and when the proportion of human CD45 positive cells in the peripheral blood of the mice reached 5%, the leukemia cells were considered to have been successfully implanted, and the divided administration was started.
The inhibitor was administered for 4 weeks in a continuous manner in the manner described above, and the ratio of human CD45 and CD33 double-positive cells in the bone marrow of each group of mice after the completion of administration was examined, to obtain the results shown in fig. 6A to 7B. Wherein FIGS. 6A and 6B are two different patient samples, FIG. 7A is the ratio of human CD45 positive cells in mouse bone marrow, and FIG. 7B is the number of human CD45 positive cells in mouse bone marrow; AML # 3 and AML # 14 represent mouse leukemia models constructed from two different patient specimens.
As shown in fig. 6A-6B and fig. 7A-7B, both the proportion and number of leukemic cells (human CD45 positive cells) were significantly reduced in mice treated with the combined inhibitor consisting of FLT3 inhibitor AC220 and histone deacetylase 8 specific inhibitor 22 d.
Survival time was observed for each group of mice after completion of administration to obtain survival curves as shown in FIG. 8, in which AML # 3 and AML # 14 represent mouse leukemia models constructed from two different patient specimens.
As can be seen from fig. 6A to 8, targeting FLT3 and histone deacetylase 8 simultaneously significantly reduced the proportion and number of leukemia cells (human CD45 positive cells) in mice, and the survival time was also significantly prolonged. That is, the use of the combined inhibitor consisting of the FLT3 inhibitor AC220 and the histone deacetylase 8 specific inhibitor 22d can significantly reduce the proportion and number of leukemia cells (human CD45 positive cells) in mice and significantly prolong the survival time of mice, more than the use of the FLT3 inhibitor AC220 or the histone deacetylase 8 specific inhibitor 22d alone.
In the invention, by utilizing the specific inhibitor of histone deacetylase 8, the resistance mechanism that the expression of histone deacetylase 8 is up-regulated by leukemia cells to resist the FLT3 inhibitor is eliminated, so that the FLT3-ITD positive acute myelogenous leukemia is more effectively treated.
The present invention has been described in relation to the above embodiments, which are only exemplary of the implementation of the present invention. It must be noted that the disclosed embodiments do not limit the scope of the invention. Rather, modifications and equivalent arrangements included within the spirit and scope of the claims are included within the scope of the invention.
Claims (8)
1. A combination inhibitor comprising a histone deacetylase 8 specific inhibitor and an FLT3 inhibitor.
2. The pharmaceutical composition of claim 1, wherein the FLT3 inhibitor comprises a compound of formula I:
3. the combination inhibitor of claim 1, wherein the histone deacetylase 8-specific inhibitor is a histone deacetylase 8-specific inhibitor 22 d.
4. An inhibitor of an FLT3-ITD mutant, comprising a histone deacetylase 8 specific inhibitor and an FLT3 inhibitor.
5. The FLT3-ITD mutant inhibitor according to claim 3, wherein the FLT3 inhibitor comprises a compound of formula I:
6. use of a combination inhibitor according to claim 1 for the preparation of an inhibitor for the synergistic inhibition of FLT3-ITD mutants.
7. Use of a combination inhibitor according to claim 1 or an FLT3-ITD mutant inhibitor according to claim 3 in the manufacture of a medicament for the treatment of acute myeloid leukaemia.
8. Use of a combination inhibitor according to claim 1 or an inhibitor of the FLT3-ITD mutant according to claim 3 in the manufacture of a medicament for the treatment of acute myeloid leukemia positive for FLT3-ITD mutations.
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