CN117298281A - Combination of gossypol acetate and CDK4/6 inhibitor - Google Patents
Combination of gossypol acetate and CDK4/6 inhibitor Download PDFInfo
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- CN117298281A CN117298281A CN202311118684.0A CN202311118684A CN117298281A CN 117298281 A CN117298281 A CN 117298281A CN 202311118684 A CN202311118684 A CN 202311118684A CN 117298281 A CN117298281 A CN 117298281A
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Abstract
The invention discloses a combination drug of gossypol acetate and a CDK4/6 inhibitor, and relates to the technical field of medicines. The pharmaceutical composition comprises a CDK6 negative modulator and a CDK4/6 inhibitor; the CDK6 negative regulator comprises gossypol acetate or baicalein derivatives. The invention provides a combined treatment scheme of gossypol acetate and CDK4/6 inhibitor or a treatment scheme of baicalein derivative combined with CDK4/6 inhibitor, which shows excellent synergistic effect and can effectively improve the treatment effect of a patient insensitive to CDK4/6 inhibitor.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a combination medicament of gossypol acetate and a CDK4/6 inhibitor.
Background
Cancer is a major disease causing human death, and the number of cancer deaths worldwide is about 700 ten thousand per year. At present, due to the defects of early diagnosis and screening technology of cancers, a large part of cancer patients are already in the late stage of tumors when first-time treatment is carried out, and the opportunity of surgical excision cure is lost. Chemotherapy and radiotherapy remain the primary treatment for advanced tumors at this stage. However, this method of treatment has limited efficacy and most patients eventually relapse, and in addition, this method has very large side effects, greatly reducing the quality of life of the patient.
The tumor targeting therapy is aimed at functional molecules specifically expressed by tumors, and targeted inhibitors including antibodies, small molecules, biological carriers and the like are designed and developed. The targeting molecule can specifically inhibit the growth, movement, chemotherapy resistance and other functions of tumor cells, and has no destructive effect on normal tissue cells. Therefore, the targeted therapy can greatly prolong the survival time and the survival quality of the patient. Cyclin-dependent kinase4/6 (CDK 4/6) is a tumor therapeutic target that has become a research hotspot for nearly two years, and 3 CDK4/6 inhibitors have been approved by the FDA for tumor therapy at this stage, namely Palbociclib (Pabociclib), ribocicib (Rabociclib) and Abemacilib (2017) for three drug sales in total of approximately $33 billion. CDK4/6 is a key factor for regulating the cell cycle, can trigger the cell cycle to change from a growing period (G1 period) to a DNA replication period (S period), has strong selectivity on CDK4/6, and blocks CDK4/6-Rb channels by inhibiting Rb protein phosphorylation, so that tumor cells are induced to stagnate in the G1 period, and further, the effect of inhibiting tumor cell proliferation is achieved.
However, such CDK4/6 inhibitors have the following disadvantages: first, the kinase inhibitors only inhibit kinase activity of CDK4/6 protein, but CDK6 protein has stronger transcriptional activity, and can promote cell cycle progress and angiogenesis in a kinase independent manner; second, clinical trial results show that there are a large number of patients insensitive to such kinase inhibitors, whereas high expression of CDK6 protein is one of the major reasons for clinical insensitivity. Thus CDK4/6 inhibitors alone are not sufficient to completely inhibit the carcinomatous function of CDK 4/6.
In view of the above-mentioned shortcomings of CDK4/6 inhibitors, there is an ongoing effort in the art to find combinations that can have a synergistic effect with CDK4/6 inhibitors to further enhance the therapeutic effects of cancer, particularly in patients not sensitive to CDK4/6 inhibitors.
Disclosure of Invention
The invention aims to provide a combined medicament of a baicalein derivative and a CDK4/6 inhibitor, and provides a combined treatment scheme of the baicalein derivative and the CDK4/6 inhibitor or a treatment scheme of combining the baicalein derivative and gossypol acetate with the CDK4/6 inhibitor, which shows excellent synergistic effect and can effectively improve the treatment effect of a patient insensitive to the CDK4/6 inhibitor.
The technical scheme adopted by the invention for achieving the purpose is as follows:
a pharmaceutical composition comprising a CDK6 negative modulator and a CDK4/6 inhibitor. The invention is based on a large number of experiments to find that LRPPRC (leucine-rich triangular pentapeptide repetitive motif protein) is a key regulatory protein for CDK6 protein expression; LRPPRC directly binds and stabilizes the mRNA of CDK6, resulting in high expression of CDK6 protein. Meanwhile, the screened LRPPRC specific small molecule inhibitor gossypol acetate (GAA) can directly inhibit the combination of LRPPRC protein and mRNA of CDK6 to reduce the stability of the latter, and can directly degrade the LRPPRC protein to further inhibit the expression and cell cycle of CDK6 protein. Based on the above, the invention provides that the combination of the inhibitor GAA of LRPPRC and the CDK4/6 inhibitor can play a stronger role in tumor inhibition. Meanwhile, the invention further provides that the combination of the baicalein derivative, GAA and the CKD4/6 kinase inhibitor can obviously inhibit the growth and the clonogenic capacity of cancer cells, and has stronger inhibition effect and synergistic enhancement compared with the single medicine.
In particular, the CDK6 negative modulator comprises at least one of an active agent that directly or indirectly reduces the stability of CDK6mRNA, an active agent that promotes the degradation of CDK6mRNA, and an active agent that reduces the level of CD6K protein.
Specifically, the CDK6 negative modulator comprises gossypol acetate and/or baicalein derivatives.
In particular, CDK4/6 inhibitors include Palbociclib, ribociclib or Abemaciclib.
Further, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
The invention discloses application of baicalein derivatives in preparation of an inhibitor for binding LRPPRC and CDK6 mRNA.
The invention also discloses the use of baicalein derivatives for the preparation of a formulation for reducing CDK6mRNA stability and/or promoting CDK6mRNA degradation and/or reducing CD6K protein levels.
The invention also discloses application of the baicalein derivative and the gossypol acetate in preparing an antitumor activity synergist of the CDK4/6 inhibitor.
The invention also discloses application of the baicalein derivative and the gossypol acetate combined with the CDK4/6 inhibitor in preparing medicaments for preventing or treating tumor diseases.
The invention also discloses application of the baicalein derivative in preparing a CDK4/6 inhibitor antitumor activity synergist.
The invention also discloses application of the baicalein derivative combined with the CDK4/6 inhibitor in preparing medicaments for preventing or treating tumor diseases.
Specifically, the baicalein derivative comprises a product of sulfonylating baicalein with 4- (4-pyridyloxy) benzenesulfonyl chloride hydrochloride. The invention adopts 4- (4-pyridyloxy) benzenesulfonyl chloride hydrochloride to chemically modify baicalein to prepare baicalein derivatives, which shows better bioactivity and improves the anti-tumor capability; the CDK4/6 inhibitor and the CDK4/6 inhibitor are combined to show good synergistic effect and stronger inhibition effect than single drug. Presumably, the reason for this is that the synthesis of baicalein derivatives can improve the problem of low solubility, improve the pharmacological activity and expand the clinical application range; and the baicalein derivative can cause the expression inhibition and cell cycle inhibition of CDK6 protein, and the combination of the baicalein derivative and CDK4/6 inhibitor can have a stronger tumor inhibition effect. Meanwhile, the inhibition effect of the combination of the baicalein derivative, the GAA and the CDK4/6 inhibitor on tumors is better.
Further, the chemical structure of the baicalein derivative is shown as a formula I:
I。
the preparation method of the baicalein derivative comprises the following steps: mixing baicalein with 4- (4-pyridyloxy) benzenesulfonyl chloride hydrochloride, and reacting under a catalytic system to obtain baicalein derivative.
Further specifically, the preparation method of the baicalein derivative comprises the following steps:
under the protection of nitrogen, mixing baicalein and 4- (4-pyridyloxy) benzenesulfonyl chloride hydrochloride, adding anhydrous acetone, adding pyridine, stirring under ice bath condition for reaction for 0.5-1.5 h, monitoring the reaction process by Thin Layer Chromatography (TLC), adding ice water after the reaction is completed, standing for precipitation, filtering, rinsing with ice ethanol, and purifying by adopting silica gel column chromatography to obtain the baicalein derivative.
Specifically, the molar ratio of baicalein to 4- (4-pyridyloxy) benzenesulfonyl chloride hydrochloride is 1:2.1-2.6; the solid-liquid ratio of baicalein to anhydrous acetone is 0.02-0.03 g:1mL; the volume ratio of pyridine to anhydrous acetone is 0.1-0.3:1.
It is still another object of the present invention to provide the use of the above pharmaceutical composition for the preparation of eukaryotic tumor cell proliferation inhibitors.
Specifically, eukaryotic organisms include humans or mammals; the tumor cells include at least one of lung cancer cells, breast cancer cells, ductal breast cancer cells, liver cancer cells, esophageal cancer cells, colorectal cancer cells and prostate cancer cells, preferably at least one of lung adenocarcinoma cells, lung squamous carcinoma cells, breast cancer cells or ductal breast cancer cells.
Still another object of the present invention is to disclose the use of the above pharmaceutical composition for the preparation of a medicament for preventing and/or treating a neoplastic disease.
Specifically, the tumor disease includes at least one of lung cancer, breast cancer, ductal breast cancer, liver cancer, esophageal cancer, colorectal cancer and prostate cancer, preferably at least one of lung adenocarcinoma, squamous cell carcinoma of lung, breast cancer or ductal breast cancer.
Palbocilib (Palbociclib, trade name: ibrance) developed by the company of pyroxene, the first CDK4/6 inhibitor marketed worldwide, has been approved for the treatment of locally advanced or metastatic breast cancer that is hormone receptor positive (HR+), human EGFR 2 negative (HER 2-) and is currently undergoing clinical trials for the treatment of multiple indications either alone or in combination with other drugs. Ribociclib (Kisqali, trade name), developed by North Corp, is a highly selective CDK4/6 inhibitor that has been FDA approved for the first line treatment of HR+, HER 2-breast cancer. Abemaciclib (temporary non-uniform Chinese translation name, part of scholars translation: bomacillin, trade name: verzenio) was developed by Gift corporation and has been approved by the FDA for the treatment of HR+, HER 2-advanced or metastatic breast cancer.
The pharmaceutical or commercial names used herein refer only to the active ingredient thereof and should not be construed as limiting the source of the drug.
The term "carrier" or "excipient" may be any carrier and excipient conventional in the pharmaceutical arts. The choice of the particular carrier and excipient will depend on the mode of administration or type and state of disease used to treat the particular patient. The preparation of suitable pharmaceutical compositions for specific modes of administration is well within the knowledge of those skilled in the pharmaceutical arts. For example, carriers or excipients which may be pharmaceutically acceptable include carriers, excipients, diluents, fillers, solvents, supporting agents, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical arts. Flavoring agents, preservatives, sweeteners, and the like may also be included, if desired.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a combined drug of GAA and CDK4/6 inhibitor, which has obvious effect of inhibiting tumor growth and is obviously superior to the single use of the GAA and CDK4/6 inhibitor, thus showing that the combined use of the GAA and CDK4/6 inhibitor can play a synergistic effect. Meanwhile, the invention provides an action mechanism of GAA, which can inhibit the expression of CDK6 protein, and the combination of GAA and CDK4/6 inhibitor can effectively improve the treatment effect of a patient insensitive to the CDK4/6 inhibitor. Furthermore, GAA and CDK4/6 inhibitors have been shown to be useful in clinical therapy with high safety, respectively. Meanwhile, the invention also discloses a combined medicament of the baicalein derivative and/or the gossypol acetate combined CDK4/6 inhibitor, which shows stronger inhibition effect, provides a new and more effective treatment scheme for clinically treating tumor diseases, and has good clinical application prospect.
Therefore, the invention provides a combined medicament of the baicalein derivative and the CDK4/6 inhibitor, and provides a combined treatment scheme of the baicalein derivative and the CDK4/6 inhibitor or a treatment scheme of combining the baicalein derivative and the gossypol acetate with the CDK4/6 inhibitor, which shows excellent synergistic effect and can effectively improve the treatment effect of a patient insensitive to the CDK4/6 inhibitor.
Drawings
FIG. 1 shows the results of measurement of the degree of mRNA enrichment of CDK 6;
FIG. 2 is a western blot detection of CDK6 and LRPPRC proteins in lung adenocarcinoma cell line A549, wherein the hybridization signal of the Actin protein was used as an internal reference for measuring the loading;
FIG. 3 is a graph of growth rate of breast cancer cell line MCF 7;
FIG. 4 is a graph of survival detection of lung adenocarcinoma cell line A549;
FIG. 5 is a graph of survival assay for lung cancer cell line H1299;
fig. 6 is a microscopic image of breast cancer cell line BT474 and breast cancer cell line MCF 7.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the following describes in detail various embodiments of the present invention with reference to the embodiments. However, those of ordinary skill in the art will understand that in various embodiments of the present invention, numerous technical details have been set forth in order to provide a better understanding of the present application. However, the technical solutions claimed in the present application can be implemented without these technical details and with various changes and modifications based on the following embodiments.
Example 1:
GAA inhibitor LRPPRC interactions with CDK6
Through RNA immunoprecipitation experiments (RNA Immunoprecipitation), GAA was demonstrated to inhibit the binding of mRNA of CDK6 to LRPPRC protein. The experimental procedure was as follows:
(1) And (3) performing pancreatin digestion to collect a lung adenocarcinoma cell line A549, lysing cells to extract cell lysate, and respectively adding GAA with a final concentration of 10 mu M into the cell lysate to take a sample added with DMSO as a blank control group (NC group).
(2) Mu.g of LRPPRC antibody (abcam, cat# ab 97505) and 50. Mu.L protein A/G beads were added to each tube and incubated overnight on a four-degree carousel. After incubation, washing with PBS buffer solution, extracting mRNA enriched on protein A/G magnetic beads, carrying out real-time fluorescence PCR after reverse transcription, detecting the enrichment degree of mRNA of CDK6, and carrying out normalization statistical analysis by using the enrichment amount of a DMSO-treated sample. The results of the tests are shown in fig. 1 (significance is expressed in the x of each experimental group compared with NC group, P-value < 0.05 is expressed as x, and P-value < 0.01 is expressed as x).
(3) Culturing a lung adenocarcinoma cell line A549 in a culture dish with the diameter of 100mm, respectively adding GAA (0 mu M,5 mu M, 10 mu M and 20 mu M) with concentration gradient when the cell concentration is about 60%, culturing the cells, and collecting the cells after 48 hours. And (3) extracting cell proteins, carrying out Western blot experiments on 40 mu g of total proteins after protein quantification, detecting protein expression levels of CDK6 and LRPPRC, and taking hybridization signals of the Actin proteins as internal references for measuring sample loading quantity. The Western blot detection results are shown in FIG. 2.
As can be seen from fig. 1, the mRNA binding of CDK6 to LRPPRC was significantly reduced upon addition of GAA. From the analysis of fig. 2, protein levels of both LRPRPC and CDK6 were significantly reduced after GAA treatment. It was demonstrated that GAA can affect CDK6 protein expression by blocking LRPPRC binding to mRNA of CDK 6.
Example 2:
inhibition of tumor growth rate by GAA in combination with CDK4/6 inhibitors
Cell growth rate curves were examined in breast cancer cell line MCF7 treated with CDK4/6 inhibitor Palbociclib, GAA and both in combination (PBS buffer alone as control).
The test results are shown in fig. 3, wherein Palbociclib, GAA alone slows the growth rate of cells but does not completely inhibit the growth of cells, and when used in combination, the cell growth rate is completely inhibited.
Example 3:
the combination of GAA and CDK4/6 inhibitor has synergistic effect
Lung adenocarcinoma cell line a549 and lung carcinoma cell line H1299 in logarithmic growth phase were counted by pancreatin digestion and seeded in 96-well plates at a density of 2000/well and after 24H of incubation the following reagents were added, respectively: four groups are set up, namely a combined group with the addition of GAA (5 mu M), palbocicilib (40 mu M) and GAA (5 mu M) +Palbocicilib (40 mu M), so that the group with the addition of PBS buffer solution is used as a blank control group. After further culturing for 48 hours, cell viability was determined using the MTS method and the inhibition rates for each group were calculated.
The results of the cell viability assay are shown in FIG. 4, wherein the cell viability of each group was characterized by a cell viability of 1.0 for the blank group.
The standard synergy index calculation formula Q=E (A+B)/(E (A) +E (B) -E (A). Times.E (B)), (E (A+B) is the inhibition rate of the combination of two drugs, E (A) is the inhibition rate of the single drug A, E (B) is the inhibition rate of the single drug B) is adopted to carry out the synergy statistics of GAA and Palbocicilib, and when the Q value is more than 1.15, the synergy is obtained. E (GAA) =0.36, E (Palbociclib) =0.39, E (gaa+palbociclib) =0.73, q=1.20 in lung adenocarcinoma cell line a549, showed a synergistic effect. E (GAA) =0.35, E (Palbociclib) =0.09, E (gaa+palbociclib) =0.66, q=1.66 in lung cancer cell line H1299, showed a synergistic effect.
Example 4:
inhibition of tumor clonogenic by GAA in combination with CDK4/6 inhibitors
Breast cancer cell line BT474 and breast cancer cell line MCF7 in logarithmic growth phase were individually inoculated into normal 96-well plates at 2000 pieces/well, and after 24h adherence, the following reagents were added: four groups are set up, namely a combined group with the addition of GAA (5 mu M), palbocicilib (40 mu M) and GAA (5 mu M) +Palbocicilib (40 mu M), so that the group with the addition of PBS buffer solution is used as a blank control group. After further culturing for 48 hours, the cells were washed with PBS buffer, fixed with methanol for 5 minutes, 0.5% crystal violet staining solution was added, and after 10 minutes staining, the cells were thoroughly washed, and imaging images of each group of cells were collected under a microscope.
The image acquisition results are shown in fig. 5. From the analysis of FIG. 5, it was found that Palbociclib, GAA alone reduced the number of clones of cells, which, when combined, could be inhibited by more than 95%, further demonstrating the good synergistic effect of GAA in combination with CDK4/6 inhibitors.
Example 5:
baicalein derivative and CDK4/6 inhibitor combined use have synergistic effect
Preparation of baicalein derivatives:
under the protection of nitrogen, baicalein and 4- (4-pyridyloxy) benzenesulfonyl chloride hydrochloride (the molar ratio of the baicalein to the anhydrous acetone is 1:2.5) are taken and mixed, anhydrous acetone (the solid-liquid ratio of the baicalein to the anhydrous acetone is 0.026g:1 mL) is added, pyridine (the volume ratio of the baicalein to the anhydrous acetone is 0.2:1) is then added, the mixture is placed under the ice bath condition for stirring reaction for 1h, the reaction progress is monitored by Thin Layer Chromatography (TLC), ice water is added for standing and precipitating after the reaction is finished, filtering and ice-ethanol rinsing are carried out, and then silica gel column chromatography purification (the eluent is methylene dichloride) is adopted to obtain the baicalein derivative, wherein the chemical structure is as follows:
1 H NMR(400 MHz,CDCl 3 ):δ:8.41、7.06(8H,Py-H),7.45~7.80(13H,Ar-H),6.69(s,1H,C=CH),5.87(s,1H,Ar-H)。
synergistic effect investigation
Lung adenocarcinoma cell line a549 and lung carcinoma cell line H1299 in logarithmic growth phase were counted by pancreatin digestion and seeded in 96-well plates at a density of 2000/well and after 24H of incubation the following reagents were added, respectively: four groups are set up, namely a combined group with the addition of baicalein derivatives (5 mu M), palbociclib (40 mu M) and baicalein derivatives (5 mu M) +Palbociclib (40 mu M), and the group with the addition of PBS buffer solution is used as a blank control group. After further culturing for 48 hours, cell viability was determined using the MTS method and the inhibition rates for each group were calculated. Cell viability assay results the cell viability of each group was characterized by a cell viability of 1.0 for the blank group.
The standard synergy index calculation formula Q=E (A+B)/(E (A) +E (B) -E (A). Times.E (B)), (E (A+B) is the inhibition rate of the combination of two drugs, E (A) is the inhibition rate of the single drug A, and E (B) is the inhibition rate of the single drug B) is adopted to carry out the synergy statistics of the baicalein derivative and the Palbociclib, and the synergy is when the Q value is more than 1.15. E (baicalein derivative) =0.31, E (Palbociclib) =0.39, E (baicalein derivative+palbociclib) =0.82, q=1.42 in lung adenocarcinoma cell line a549, showed a synergistic effect. E (baicalein derivative) =0.27, E (Palbociclib) =0.09, E (baicalein derivative+palbociclib) =0.73, q=2.17 in lung cancer cell line H1299 showed a synergistic effect.
Example 6:
baicalein derivative, GAA and CDK4/6 inhibitor combined with synergistic effect
The baicalein derivative was prepared in the same manner as in example 5.
Lung adenocarcinoma cell line a549 and lung carcinoma cell line H1299 in logarithmic growth phase were counted by pancreatin digestion and seeded in 96-well plates at a density of 2000/well and after 24H of incubation the following reagents were added, respectively: four groups are set, namely a combined group of GAA (2.5 mu M) +Palbociclib (30 mu M), a combined group of baicalein derivatives (2.5 mu M) +Palbociclib (30 mu M) and a combined group of GAA (2.5 mu M) +baicalein derivatives (2.5 mu M) +Palbociclib (30 mu M), and a group added with PBS buffer solution is used as a blank control group. After further culturing for 48 hours, cell viability was determined using the MTS method and the inhibition rates for each group were calculated. Cell viability assay results the cell viability of each group was characterized by a cell viability of 1.0 for the blank group.
And (3) adopting a standard synergy index calculation formula Q=E (A+B)/(E (A) +E (B) -E (A). Times.E (B)), (E (A+B) is the inhibition rate of three-drug combination, E (A) is the inhibition rate of combination of GAA and Palbociclib, E (B) is the inhibition rate of combination of baicalein derivative and Palbociclib), and the synergy statistics of baicalein derivative, GAA and Palbociclib are carried out, and the synergy is achieved when the Q value is greater than 1.15. E (gaa+palbociclib) =0.33, E (baicalein derivative+palbociclib) =0.39, E (baicalein derivative+gaa+palbociclib) =0.94, q=1.59 were shown to be synergistic effects in lung adenocarcinoma cell line a 549. In lung cancer cell line H1299E (gaa+palbociclib) =0.24, E (baicalein derivative+palbociclib) =0.31, E (baicalein derivative+gaa+palbociclib) =0.91, q=1.91, showed a synergistic effect.
In the examples, lung adenocarcinoma, lung cancer, and breast cancer cells were taken as examples, but of course, colon cancer, rectal cancer, esophageal cancer, squamous cell carcinoma of the lung, pancreatic cancer, and gastric cancer may be taken, and the examples are not limited thereto.
The conventional technology in the above embodiments is known to those skilled in the art, and thus is not described in detail herein.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A pharmaceutical composition comprising a CDK6 negative modulator and a CDK4/6 inhibitor.
2. The pharmaceutical composition of claim 1, wherein the CDK6 negative modulator comprises at least one of an active agent that directly or indirectly reduces CDK6mRNA stability, an active agent that promotes CDK6mRNA degradation, and an active agent that reduces CD6K protein levels.
3. The pharmaceutical composition of claim 2, wherein the CDK6 negative modulator comprises gossypol acetate and/or a baicalein derivative.
4. The pharmaceutical composition of claim 1, wherein the CDK4/6 inhibitor comprises Palbociclib, ribociclib or Abemaciclib.
5. Use of a baicalein derivative in the preparation of an inhibitor of LRPPRC and CDK6mRNA binding.
6. Use of a baicalein derivative in the preparation of a formulation for reducing CDK6mRNA stability and/or promoting CDK6mRNA degradation and/or reducing CD6K protein levels.
7. The application of baicalein derivatives in preparing CDK4/6 inhibitor antitumor activity synergist is provided.
8. Use of a baicalein derivative in combination with a CDK4/6 inhibitor for the preparation of a medicament for the prevention or treatment of a neoplastic disease.
9. The use of the pharmaceutical composition according to any one of claims 1 to 4 for preparing a eukaryotic tumor cell proliferation inhibitor.
10. The use of the pharmaceutical composition according to any one of claims 1 to 4 for the preparation of a medicament for the prevention and/or treatment of neoplastic diseases.
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