FOXP4 protein inhibitor as well as pharmaceutical composition and application thereof

Abstract

The invention relates to a compound as shown in a formula I, which can be used as an FOXP4 protein inhibitor, and a pharmaceutical composition and application thereof, in particular to application in treatment of gastric cancer.

Description

Technical Field

[0001] This application belongs to the field of medicinal chemistry, specifically relating to compounds that can be used as inhibitors of the FOXP4 protein, methods for their preparation, and pharmaceutical compositions comprising said compounds. This application also relates to the therapeutic use of said compounds or pharmaceutical compositions thereof in tumors. Background Technology

[0002] FOXP4 (Forkhead box protein P4) is a member of the FOXP protein family. It is abnormally highly expressed in colorectal cancer, non-small cell lung cancer, hepatocellular carcinoma, and breast cancer, exhibiting characteristics of an oncogene. As a transcription factor, FOXP4 is highly expressed in both cancer cells and tissues and is closely related to patient prognosis. Developing novel FOXP4 modulators and investigating their role in the prevention and treatment of FOXP4-related diseases or conditions is of great significance. Summary of the Invention

[0003] On the one hand, this application provides compounds of formula I or pharmaceutically acceptable salts thereof.

[0004]

[0005] On the other hand, this application provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0006] On the other hand, this application provides the use of the compound of Formula I above or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the preparation of a treatment for the prevention or treatment of diseases or conditions related to FOXP4 protein.

[0007] On the other hand, this application provides the use of the compound of Formula I above or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the preparation of a medicament for inhibiting FOXP4 protein. Attached Figure Description

[0008] Figure 1 A schematic diagram of the binding model of the inhibitor compound of Formula I to the human FOXP4 protein is shown.

[0009] Figure 2 The inhibitory compounds of Formula I were shown to have cytotoxic effects and IC50 values ​​against gastric cancer cells MKN28 and NCI-N87. 50 value.

[0010] Figures 3A-3D The inhibitory effects of the Formula I inhibitory compound on the proliferation of gastric cancer cells MKN28 and NCI-N87 were demonstrated (growth capacity assay and colony formation assay).

[0011] Figures 4A-4CThe inhibitory compound of Formula I was shown to induce apoptosis in MKN28 and NCI-N87 cells.

[0012] Figure 5 The proton NMR spectrum of the compound of formula I is shown.

[0013] Figure 6 The mass spectrum of the compound of formula I is shown. Detailed Implementation

[0014] definition

[0015] The following definitions and methods are provided to better define this application and to guide those skilled in the art in its practice. Unless otherwise stated, the terms are to be understood in accordance with their conventional usage by those skilled in the art. All patent documents, academic papers, and other published materials cited herein are incorporated herein by reference in their entirety.

[0016] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0017] (i) Suppress the disease or disease state, that is, curb its development;

[0018] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0019] The term "prevention" means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with said disease, and includes:

[0020] Preventing the occurrence of disease or disease state in subjects (e.g., mammals), especially when such subjects are susceptible to the disease state but have not yet been diagnosed with it.

[0021] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0022] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid and free base of a specified compound and has no adverse effects on biology or otherwise. "Pharmaceutically acceptable salt" includes "pharmaceutically acceptable acid adduct salt" and "pharmaceutical acceptable base adduct salt".

[0023] The term "pharmaceutical composition" refers to a bioactive compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to excipients, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound of this application to an organism.

[0024] In this disclosure, the terms "object" or "individual" include both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domesticated animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish.

[0025] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0026] The term "carrier" refers to a relatively non-toxic chemical compound or reagent that helps to introduce the compound into cells or tissues.

[0027] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, lozenges, ointments, syrups, emulsions, suspensions, solutions, suppositories, injections, inhalers, gels, microspheres and aerosols, etc.

[0028] Typical routes of administration or delivery of the compounds of this application and their pharmaceutically acceptable salts include, but are not limited to, oral, rectal, transmucosal, topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. Preferred routes of administration are oral and injectable administration.

[0029] The pharmaceutical composition of this application can be prepared using methods known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, and freeze-drying.

[0030] In some embodiments, the pharmaceutical compositions of this application are in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients or excipients well known in the art. These excipients or excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, powders, granules, liquids, syrups, emulsions, gels, pastes, suspensions, etc., for oral administration to patients.

[0031] Solid pharmaceutical compositions suitable for oral administration can be prepared using conventional mixing, filling, or tableting methods. For example, an oral composition in solid form can be obtained by mixing an active compound with a solid excipient or excipient, optionally milling the resulting mixture, adding other suitable excipients or excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients or excipients include, but are not limited to, fillers, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0032] The pharmaceutical compositions of this application are also suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions, emulsions, or lyophilized products. Appropriate excipients, such as fillers, buffers, or surfactants, can be used.

[0033] In all methods of administration of the compounds or compositions described herein, the daily dose may be, for example, 0.001-300 mg / kg body weight, such as 0.01-300 mg / kg body weight, or 10-200 mg / kg body weight, administered in a single dose or in separate doses.

[0034] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0035] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0036] Some compounds in this application may have asymmetric carbon atoms (stereocenters) or double bonds. Therefore, racemates, diastereomers, enantiomers, geometric isomers, and monomeric isomers are all included within the scope of this application.

[0037] When the compounds of this application contain alkene double bonds or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified.

[0038] The compounds of this application may exist in specific geometric or stereoisomer forms. This application envisions all such compounds, including tautomers, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0039] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of this application, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0040] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0041] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0042] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, wherein deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium, and all such compounds are included within the scope of this application.

[0043] This application describes the development of an AQP4 inhibitor targeting AQP4 for the treatment of gastric cancer.

[0044] On the one hand, this application provides compounds of formula I or pharmaceutically acceptable salts thereof.

[0045]

[0046] On the other hand, this application provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or excipient.

[0048] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0049] On the other hand, this application provides the use of the compound of Formula I above or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the preparation of a treatment for the prevention or treatment of diseases or conditions related to FOXP4 protein.

[0050] In some implementations, the disease or condition associated with the FOXP4 protein is a disease or condition that benefits from the inhibition of FOXP4 protein expression.

[0051] In some implementations, the disease or condition is stomach cancer.

[0052] On the other hand, this application provides the use of the compound of Formula I above or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the preparation of a medicament for inhibiting FOXP4 protein.

[0053] In another aspect, this application provides the use of the compound of Formula I above or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in the prevention or treatment of diseases or conditions related to FOXP4 protein.

[0054] On the other hand, this application provides the use of the compound of Formula I above or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in inhibiting FOXP4 protein (including but not limited to inhibiting the expression and activity of FOXP4 protein).

[0055] On the other hand, this application provides a method for preventing or treating diseases or conditions related to the FOXP4 protein, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula I as described in this disclosure or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition.

[0056] On another front, this application provides a method for inhibiting the FOXP4 protein, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula I as described in this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method for inhibiting the FOXP4 protein includes in vitro or in vivo inhibition.

[0057] On the other hand, this application provides compounds of formula I as described in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases or conditions related to FOXP4 protein.

[0058] In another aspect, this application provides a compound of formula I as described in this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for inhibiting FOXP4 protein.

[0059] On the other hand, this application provides compounds of formula I as described in this disclosure or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of gastric cancer.

[0060] The inventions of this application provide one or more of the following advantages:

[0061] 1. The compounds disclosed herein have excellent FOXP4 inhibitory activity, which can inhibit FOXP4 and thus inhibit tumor cell proliferation, and can be used to inhibit gastric cancer cells with high FOXP4 expression.

[0062] 2. The compounds disclosed herein exhibit high selectivity, strong targeting, and / or strong affinity for cancer cells, particularly gastric cancer cells. The drug specificity of the compounds disclosed herein was determined by immunofluorescence staining and flow cytometry.

[0063] Example

[0064] The specific implementation methods of this disclosure will be further described in detail below with reference to the embodiments. The following embodiments are for illustrative purposes only and are not intended to limit the scope of this application.

[0065] Preparation Example 1

[0066] Synthesis of compounds of formula I:

[0067]

[0068] Preparation method:

[0069] 1. Protection of functional groups: Starting with lapamycin, use appropriate protecting groups (including Ac, Bn, TBDMS) to protect any reactive functional groups to prevent unexpected reactions in subsequent steps.

[0070] 1.1 Starting material: Lapamycin, 1.0 g (approximately 1.1 mmol).

[0071] 1.2 Protecting groups: Acetic anhydride (Ac2O): used to protect hydroxyl groups; benzyl alcohol (BnOH): used to protect alcohol groups; tert-butyldimethylchlorosilane (TBDMS-Cl): used to protect phenolic groups.

[0072] 1.3 Reaction solvent: Dichloromethane (DCM), 50 mL.

[0073] 1.4 Reaction conditions: At room temperature, 4-dimethylaminopyridine (DMAP) was used as a catalyst. The amount of each protecting group was calculated based on the molar amount of lapamycin and was 1.5 times excess. Lapamycin was reacted with the above protecting groups in the above reaction solvent for 12 hours.

[0074] 1.5 Purification method: The protected lapamycin was purified by column chromatography (using silica gel as the stationary phase and petroleum ether and ethyl acetate in a volume ratio of 4:1 as the eluent).

[0075] 2. Introduction of the oxazole group: The protected lapamycin was dissolved in a suitable solvent, and then 2-azidotetrazole, a reagent containing the oxazole group, was added under controlled reaction conditions. The reaction progress was closely monitored and the product was purified to obtain the oxazole-modified intermediate.

[0076] 2.1 Reactants: Protected lapamycin, 0.5 g (approximately 0.5 mmol).

[0077] 2.2 Oxazolyl reagent: 2-azidotetrazol, 0.55 g, about 3 mmol.

[0078] 2.3 Solvent selection: N,N-dimethylformamide (DMF), 20 mL.

[0079] 2.4 Reaction conditions: First, stir at 0℃ for 1 hour, then raise the temperature to room temperature and continue the reaction for 12 hours.

[0080] 2.5 Monitoring and Purification: The reaction progress was monitored by thin-layer chromatography (TLC). After completion, the oxazole-modified intermediate was purified by column chromatography (using silica gel, petroleum ether and ethyl acetate in a 2:1 volume ratio as eluent).

[0081] 3. Deprotection: Since protecting groups were used in the first step, they are selectively removed to obtain the final product. This step may involve the use of specific reagents and conditions for the protecting groups used. Specifically:

[0082] 3.1 Collect 0.45 g (approximately 0.4 mmol) of the oxazole-modified intermediate, which had been successfully synthesized and purified.

[0083] 3.2 Prepare a solvent system by mixing methanol and water at a 1:1 volume ratio, with a total volume of 30 mL. Dissolve the intermediate in this solvent.

[0084] 3.3 Add a deprotecting agent to remove the protecting group introduced in the first step. The choice of deprotecting agent will depend on the specific protecting group used. For acetyl (Ac) protecting groups, alkaline conditions, i.e., sodium bicarbonate (NaHCO3) solution, are required. Specifically, add 20 mL of 1M sodium bicarbonate (NaHCO3) solution to remove the acetyl protecting group and stir at room temperature for 24 hours. Subsequently, adjust the pH of the reaction system to neutral, extract the organic phase with ethyl acetate, dry and concentrate. The main purpose of this step is to remove the acetyl protecting group under mild alkaline conditions without affecting other sensitive groups. Next, for the removal of the benzyl protecting group, use 10% palladium on carbon (Pd / C) as a catalyst per 20 mL of reaction solution system and reduce under a hydrogen atmosphere at atmospheric pressure for 12 hours. This step is carried out at room temperature and should be performed only after ensuring that the acetyl protecting group has been completely removed in the previous step to avoid unnecessary side reactions. Subsequently, adjust the pH to neutral again, extract the organic phase, and dry it to prepare for the next step. Finally, the removal of the tert-butyldimethylsilane protecting group was carried out by adding tetrabutylammonium fluoride (TBAF). The 1M TBAF solution was prepared using dimethyl sulfoxide as the solvent. Specifically, three times the molar amount of TBAF equivalent to the TBDMS protecting group was added to the reaction solution. Assuming the TBDMS protecting group is 1 mmol, 3 mL of 1M TBAF solution was required, and the mixture was stirred at room temperature for 4–6 hours. The final compound was obtained by column chromatography (silica gel, petroleum ether, and ethyl acetate in a 1:1 volume ratio).

[0085] 3.4 After the reaction was completed, mass spectrometry and proton NMR were used to confirm the structure of the product, ensuring successful removal of the protecting group and obtaining the final compound of formula I. Figure 5 and Figure 6 The proton and mass spectra of the compounds of formula I are shown respectively.

[0086] Example 1

[0087] The IC50 of FOXP4 inhibitor compounds on gastric cancer cells was detected using the CCK8 assay. 50 The inhibitory effect of FOXP4 inhibitor compounds on gastric cancer cells was detected by plate colony formation assay. Apoptosis assay showed that FOXP4 inhibitor compounds of formula I induced apoptosis in gastric cancer cell lines in a concentration-dependent manner.

[0088] 1. Experimental materials.

[0089] 1.1 Cell lines: Human gastric cancer cell lines MKN28 and NCI-N87.

[0090] 1.2 Experimental reagents: RPMI-1640 medium, trypsin, fetal bovine serum, 0.04% crystal violet, CCK8 reagent, and apoptosis detection kit.

[0091] 2. Experimental methods.

[0092] 2.1 Cell Proliferation CCK8 Assay: In this experiment, logarithmic growth phase gastric cancer cells MKN28 and NCI-N87 were seeded at a density of 3000 cells / well in 96-well plates. Cells were then treated with different concentrations of compound I for 48 hours, followed by replacement with 100 μl of fresh culture medium, and then 8 μl of CCK8 (from MCE Chemicals) was added to each well for 1 hour. The absorbance (OD value) at 450 nm was measured using a multi-mode microplate reader. Each group had three replicates, with the control group containing an equal volume of culture medium, and blank wells containing neither cells nor the test substance. Cell viability = (OD value of experimental wells - OD value of blank wells) / (OD value of control group - OD value of blank wells) × 100%. Figure 2 As shown.

[0093] 2.2 Cell Colony Formation Assay: MKN28 and NCI-N87 cell lines in logarithmic growth phase were carefully washed with 1×PBS buffer. Cells were digested with an appropriate amount of trypsin, counted using a counting chamber, and diluted to 1000 cells / well with culture medium. 1000 cells were added to 2 mL of culture medium, thoroughly mixed, and then added to six-well plates. Different concentrations of compound I were added to maintain equilibration, and the cells were placed in a cell culture incubator. After 7 days of continuous culture, cell colony formation was observed, and the medium was changed. Fresh culture medium was added again, and the cells were cultured for another 7 days. The culture dishes were then removed. The culture medium was removed, and the cells were carefully washed twice with 1×PBS buffer and fixed with 4% paraformaldehyde for 20 min. The cells were then carefully washed twice with 1×PBS buffer, covered with crystal violet, and stained for 10 min. Finally, after two careful washes with 1×PBS buffer, cell colony formation was observed and images were created for later statistical analysis. The results are shown below. Figures 3A-3D As shown.

[0094] 2.3 Apoptosis Assay: All cells were collected and placed in centrifuge tubes. After centrifugation, the supernatant was gently removed, and the cells were resuspended in fresh culture medium. The cells were then gently pipetted to ensure homogeneity. After dilution with tyrosine blue, cell counting was performed under a microscope using a cell counting chamber at 5 × 10⁶ cells per well. 5Cells were cultured in six-well plates and incubated overnight at 37°C in a humidified incubator with 5% CO2. Two gastric cancer cell lines, MKN28 and NCI-N87, were treated for 48 hours with different concentrations of compound I or a control (DMSO). After centrifugation at 1000g to remove the supernatant, each cell sample was resuspended in binding buffer at 1:10. The FITC Annexin V apoptosis detection kit (BD Pharmingen) was used. 10 μL of PI and 5 μL of Annexin V were added to each group, mixed thoroughly, and incubated at 37°C in the dark for 20 minutes.

[0095] Before loading, add 1 times the binding buffer to each sample, mix thoroughly, and then load the sample. Use a flow cytometer (BD Pharmingen) to sort the stained cells. Then analyze the results using FlowJo software (BD Pharmingen). The results are shown below. Figures 4A-4C As shown.

[0096] The foregoing has provided a detailed description of this disclosure using general principles and specific implementation methods. However, modifications or improvements can be made to this disclosure, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of this disclosure fall within the scope of protection claimed in this disclosure.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable carrier, excipient, or excipient.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2 or 3, in the preparation of a medicament for the prevention or treatment of diseases or conditions associated with the FOXP4 protein.

5. The use as described in claim 4, wherein the disease or condition associated with the FOXP4 protein is a disease or condition that benefits from the inhibition of FOXP4 protein expression.

6. The use as described in claim 4 or 5, wherein the disease or condition is gastric cancer.

7. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2 or 3, in the preparation of a medicament for inhibiting FOXP4 protein.

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