Epigenetic drugs for enhancing the anticancer effects of platinum antitumor agents and their applications

Abstract

The present invention discloses an epigenetic drug that enhances the anticancer effects of platinum antitumor agents and its application. The present invention first synthesizes a compound represented by formula (I), which can activate p53, increasing its protein expression and arresting cancer cells in the G2 / M phase, thereby exerting an anticancer effect. When used in combination with a platinum antitumor agent, the compound represented by formula (I) can enhance the anticancer effect of the platinum antitumor agent. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an epigenetic drug for enhancing the anti-cancer effect of a platinum anti-tumor agent and its application. Background Art

[0002] Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide, with an annual incidence of 630,000 cases and over 350,000 deaths. HNSCC is classified based on the site of tumor origin and differs in its etiology, prognosis, and genomic alterations. Oral and oropharyngeal cancers (OSCC) are some of the most common HNSCCs. It is estimated that over 300,000 people worldwide develop OSCC annually, with an overall five-year survival rate reported to be 50%-60%. An estimated 32-50% of patients will experience recurrence after initial treatment. The current standard of care for HNSCC, including OSCC, is surgical resection. If the disease is detected early, resection can result in excellent survival outcomes. Although studies suggest that OSCC progresses from atypia to atypical hyperplasia to fully invasive malignancy, most cases are discovered at an advanced stage. In these cases, surgery often results in severe disfigurement and complications, such as eating and swallowing problems. In North America and Europe, chemotherapy, particularly platinum-based agents, has been the preferred medical treatment for HNSCC patients. The cisplatin analog carboplatin, paclitaxel, and 5-fluorouracil (5-FU) are used as part of several different regimens approved in guidelines developed by the National Comprehensive Cancer Network (NCCN) for the treatment of OSCC and other HNSCC tumors. Although patients often have a good initial response, most later develop resistance.

[0003] Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are widely used in chemotherapy regimens and are effective against a variety of cancers, including testicular, ovarian, cervical, colorectal, lung, head and neck cancers, and recurrent lymphomas. They exert their clinical effects by covalently binding to DNA bases, forming intra- and interstrand DNA adducts. Cisplatin inhibits DNA replication, blocks DNA, mRNA, and protein synthesis, and activates several transduction pathways that lead to necrosis or apoptosis. Regardless of the efficacy of first-line treatment with platinum drugs such as cisplatin, they often lead to the development of chemoresistance, resulting in treatment failure. Resistance primarily results from increased DNA repair processes and decreased apoptosis. The tumor suppressor p53 functions primarily as a transcriptional activator of numerous cellular programs, including checkpoint activation, DNA repair, and apoptosis; therefore, p53 status is crucial for the cytotoxicity of platinum drugs. Loss or mutations of p53 are common in patients, and p53 dysfunction can lead to failure of checkpoint responses, cell cycle arrest, programmed cell death (apoptosis), and permanent cell cycle arrest (senescence). Ultimately, it can lead to poor response to platinum-based chemotherapy.

[0004] Studies have shown that the status of p53 is crucial for the cytotoxicity of platinum drugs (see Ahmed AshourAhmed, et.al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J. Pathol. 221(1), 49–56; N. Stransky, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333(6046), 1157–1160; M. Gadhikar, et.al. Chk1 / 2 inhibition overcomes the cisplatin resistance of head and neck cancer cells secondary to the loss of functional p53. Mol. Cancer Ther. 12(9), 1860–1873; “M. Martinez-Rivera, et.al. Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53. Biochem. Pharmacol. 83(8), 1049-1062.), therefore, it is urgent to find a method to enhance the role of p53 to overcome the resistance of platinum drugs and enhance the sensitivity of head and neck squamous cell carcinoma to platinum drugs. Summary of the Invention

[0005] To address the shortcomings of the aforementioned prior art, the present invention provides an epigenetic drug and its application for enhancing the anticancer effects of platinum antitumor agents. The present invention first synthesizes a compound represented by formula (I), which can activate p53, increasing its protein expression, arresting cancer cells in the G2 / M phase, and thereby exerting an anticancer effect. When used in combination with a platinum antitumor agent, the compound represented by formula (I) can enhance the anticancer effect of the platinum antitumor agent, representing a new anticancer sensitization strategy with great potential for widespread application.

[0006] The first object of the present invention is to provide an epigenetic drug, characterized in that it is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; wherein the compound represented by formula (I) is named: 4-(4'-trifluoromethoxybenzyl)-7,8-dihydroxycoumarin.

[0007]

[0008] The above-mentioned epigenetic drugs are used to increase the expression of p53 protein to change the cell cycle, arrest cancer cells in the G2 / M phase, and affect the synthesis of RNA and protein.

[0009] A second object of the present invention is to provide a method for preparing an anticancer sensitization composition using the aforementioned epigenetic drug to enhance the sensitivity of a platinum antitumor agent to a tumor, thereby enhancing the antitumor effect of the platinum antitumor agent. The platinum antitumor agent is at least one of cisplatin, carboplatin, nedaplatin, cycloplatin, oxaliplatin, and lobaplatin. The tumor is at least one of lung cancer, pancreatic cancer, prostate cancer, testicular cancer, ovarian cancer, colorectal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, germ cell cancer, and lymphoma. Preferably, the tumor is head and neck cancer or colorectal cancer.

[0010] The third object of the present invention is to provide an anticancer sensitization composition, which is characterized in that it includes a platinum antitumor agent and a compound represented by formula (I).

[0011] Preferably, the molar ratio of the platinum antitumor agent to the compound represented by formula (I) is 1:1-1:3.

[0012] Preferably, when the epigenetic drug is used in combination with a platinum anti-tumor agent, the IC of the platinum anti-tumor agent can be significantly reduced in head and neck squamous cell carcinoma. 50 , and obtain better anti-tumor effects.

[0013] The anticancer sensitization composition further comprises one or more pharmaceutically acceptable carriers, including conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, and the like in the pharmaceutical field.

[0014] The anti-cancer sensitization composition can be used orally or parenterally, for example, by injection, spraying, nasal drops, eye drops, penetration, absorption, physical or chemical mediation, such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue; or can be mixed or encapsulated with other substances and then introduced into the body.

[0015] For oral administration, it can be prepared into conventional solid preparations such as tablets, powders, granules, capsules, ointments, creams, etc.; it can be prepared into liquid preparations such as aqueous or oily suspensions or other liquid preparations such as oral liquids, etc. For parenteral administration, it can be prepared into solutions for injection, aqueous or oily suspensions, etc.

[0016] The beneficial effects of the present invention are:

[0017] 1. The compound represented by formula (I) can activate p53, increase its protein expression, arrest cancer cells in the G2 / M phase, and thus exert an anti-cancer effect;

[0018] 2. When the compound represented by formula (I) is used in combination with a platinum anti-tumor agent, it can significantly enhance the sensitivity of the platinum anti-tumor agent to tumors and enhance the therapeutic effect of the platinum anti-tumor agent on platinum anti-tumor agent-resistant tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The compound represented by formula (I) 1 HNMR spectrum;

[0020] Figure 2 The compound represented by formula (I) 13 CNMR spectrum;

[0021] Figure 3 is the HR-MS spectrum of the compound represented by formula (I);

[0022] Figure 4 This is the Western blot protein band diagram of the RNA-pulldown experimental results;

[0023] Figure 5 The effect of the compound represented by formula (I), the lead compound 10-3, and compound A on the HNSCC cell cycle; wherein, blue: G0 / G1 phase, green: S phase, and red: G2 / M phase;

[0024] Figure 6 The effects of the compound represented by formula (I), the lead compound 10-3, and compound A on the expression of p53 in HNSCC cells;

[0025] Figure 7 Graph showing the anti-tumor effects of the compound represented by formula (I), lead compound 10-3, compound A, nedaplatin, and combination therapy. DETAILED DESCRIPTION

[0026] The present invention will be further described below with reference to specific examples, but this does not limit the present invention.

[0027] Unless otherwise specified, the contents of the following components are expressed in weight percentages; the experimental methods used are conventional methods; and the reagents and biological materials used are all commercially available.

[0028] The structural formula of the lead compound 10-3 (4-(4'-methoxyphenyl)-7,8-dihydroxycoumarin) used in the present invention is as follows:

[0029]

[0030] The structural formula of the lead compound A (4-(3'-trifluoromethylbenzyl)-7,8-dihydroxycoumarin, see CN2024106623279) used in the present invention is as follows:

[0031]

[0032] The platinum antitumor agent used in the present invention is nedaplatin, and its structural formula is shown below:

[0033]

[0034] Example 1: Preparation of epigenetic drugs represented by formula (I)

[0035]

[0036] Among them, a: oxalyl chloride, DMF, DCM, 37-40°C; b: Michaelis' acid (cycloisopropyl malonate), triethylamine, DCM, 0°C-rt; c: ethanol, 70-100°C; d: trifluoroacetic acid, sulfuric acid, DCM, 0°C-rt.

[0037] Its synthesis method is:

[0038] (I) The specific preparation process of the compound 4-(4'-trifluoromethoxybenzyl)-7,8-dihydroxycoumarin represented by formula (I) is as follows:

[0039] In a 100 mL single-necked reaction flask, add 4-trifluoromethoxyphenylacetic acid (5 mmol, 1 eq), oxalyl chloride (30 mmol, 6 eq), 5-6 drops of DMF, and 50 mL of anhydrous DCM. Place the mixture in a heated magnetic stirrer and reflux with stirring at 37-40°C for 1-3 h. After the reaction is complete, spin dry to obtain the crude 4-trifluoromethoxyphenylacetyl chloride, which is directly used for the next step.

[0040] At 0°C, cycloisopropyl malonate (5 mmol, 1 eq), triethylamine (12.5 mmol, 2.5 eq), and 30 mL of anhydrous DCM were placed in a 100 mL single-necked reaction flask and stirred for 10 minutes. Then, a solution of 4-trifluoromethoxyphenylacetyl chloride in anhydrous DCM was slowly added dropwise. After the addition was complete, the temperature was slowly raised to room temperature. The reaction was allowed to react overnight. The triethylamine was extracted with 0.1 mol / L citric acid solution. The organic phase was dried and spin-dried, and 60 mL of ethanol was added. The mixture was refluxed at 70-100°C for 3-5 hours. After TLC monitoring, the reaction was completed and the crude ethyl 4-trifluoromethoxyphenylacetoacetate was spin-dried to obtain the product. The crude product was purified by column chromatography (filler: silica gel powder) (eluent: petroleum ether:ethyl acetate = 15:1 by volume), followed by concentration under reduced pressure to obtain the pure product (1.16 g) as an oil.

[0041] In a 100 mL single-necked reaction flask at 0°C, H₂SO₄ (2 mmol, 2 eq) and CF₃COOH (2 mmol, 2 eq) were stirred and mixed. Then, 30 mL of anhydrous DCM, ethyl 4-trifluoromethoxyphenylacetoacetate (1 mmol, 1 eq), and pyrogallol (1.2 mmol, 1.2 eq) were added sequentially. The temperature was slowly raised to room temperature, and the reaction was continued with stirring. After 1 h, 1-2 mL of methanol was added to increase the solubility of the system. The reaction was allowed to react for 4-5 h. After completion of the reaction, as monitored by TLC, the reaction solution was extracted with saturated NaHCO₃ solution, and the organic phase was dried and spin-dried. Recrystallization was performed using ethyl acetate / petroleum ether (volume ratio 1:5). After the solid precipitate was cooled and allowed to stand, it was filtered, and the filter cake was dried in a vacuum oven to obtain 4-(4'-trifluoromethoxybenzyl)-7,8-dihydroxycoumarin (0.2 g) in a yield of 57%.

[0042] Example 2: Structural Identification

[0043] The structure of the compound was identified using HPLC-MS and BRUKER 800M NMR. The results are as follows:

[0044] The spectrum of the compound 4-(4'-trifluoromethoxybenzyl)-7,8-dihydroxycoumarin represented by formula (I) ( Figure 1-3 ) and data:

[0045] 1 H NMR (800MHz, DMSO-d6) δ: 10.09 (s, 1H), 9.33 (s, 1H), 7.45 (d, J = 9.2Hz, 2H), 7.32 (d, J =9.1Hz, 2H), 7.15 (d, J = 9.0Hz, 1H), 6.77 (d, J = 9.1Hz, 1H), 6.00 (s, 1H), 4.16 (s, 2H).

[0046] 13 C NMR (201MHz, DMSO-d6) δ: 160.26, 155.58, 149.48, 147.11, 143.64, 137.08 ,132.39,130.78,121.20,119.45,115.76,112.19,111.75,110.79,36.18.

[0047] MS: m / z (%) [M+H] + 353.0461.

[0048] Example 3: Sensitization activity assay

[0049] 1. Cell Culture

[0050] HNSCC (head and neck squamous cell carcinoma) cells were selected and cultured in DMEM medium containing 10% fetal bovine serum.

[0051] HCT116 (colon cancer cell) cells were selected and cultured in DMEM medium containing 10% serum.

[0052] All cells were purchased from Jinan Boshang Company.

[0053] 2. Cytotoxicity Test

[0054] HNSCC cells were plated in a 96-well plate at a density of 5,000-7,000 cells / 100 μL per well and cultured overnight in a cell culture incubator. After the cells adhered, 100 μL of drug-treated culture medium at varying concentrations was added and the cells were treated for a further 48 hours. The concentration gradient of the platinum antitumor agent nedaplatin was 0.78, 1.56, 3.125, 6.25, 12.5, and 25 μM. Compound I was used at a concentration of 1-10 μM. The concentration of lead compound 10-3, A was 5 μM. After 48 hours, 10 μL of MTT was added to each well and the cells were incubated at 37°C for 4 hours in the dark. The culture medium was discarded, and 150 μL of DMSO was added to each well. The cells were shaken for 10 minutes until the blue-purple crystals were completely dissolved. The absorbance at 490 nm was measured using an enzyme-linked immunosorbent assay (ELISA). Cell viability (100%) = (mean OD value of the drug group / mean OD value of the normal group) * 100%.

[0055] 3. Results Analysis

[0056] Nedaplatin monotherapy: IC 50 =1.103±0.015μM;

[0057] When compound I is used alone: ​​IC 50 =4.546±0.447μM;

[0058] When nedaplatin is used in combination with compound Ⅰ (concentration of 5 μM): IC 50 =0.501±0.014μM;

[0059] When nedaplatin was used in combination with the lead compound 10-3 (at a concentration of 5 μM): IC 50 =0.945±0.011μM;

[0060] When nedaplatin was used in combination with lead compound A (concentration of 5 μM): IC 50 =0.802±0.015μM.

[0061] It can be seen that compared with the use of nedaplatin alone and in combination with the lead compounds 10-3 and A, the compound I of the present invention has a better anti-cancer sensitization effect on nedaplatin.

[0062] Example 4: RNA-pulldown experiment

[0063] Using Pierce TM The Magnetic RNA Protein Pull-Down Kit was used to validate the mechanism of RNA pull-down experiments. The kit provides streptavidin magnetic beads and reagents for effectively enriching RNA-binding proteins. In the RNA pull-down assay, in vitro transcribed RNA is first bound to the magnetic beads. The RNA-bead complex is then incubated with cell lysate. This allows proteins bound to the target RNA to be adsorbed to the beads. After the RNA-protein complex is eluted from the beads with an elution buffer, specific bound proteins are detected by Western blotting.

[0064] 1. Experimental Plan

[0065] Binding of magnetic beads to labeled RNA: resuspend 50 μL of magnetic beads in a sterile, enzyme-free 1.5 mL centrifuge tube, place on a magnetic separation rack, and discard the supernatant; wash the magnetic beads twice with 50 μL of 20 mM Tris; resuspend the magnetic beads in 50 μL of 1× RNA Capture buffer, then add 50-100 pmol of avidin-labeled RNA (purchased from Gene Pharma), mix gently, and incubate at room temperature with shaking for 30 min.

[0066] Binding of labeled RNA to PSF protein: Place the above centrifuge tube on a magnetic separation rack, collect the magnetic beads from the side, and discard the supernatant; wash the magnetic beads twice with 50 μL of 20 mM Tris; dilute 10× protein-RNA Binding buffer to 1× with ultrapure water, and resuspend the magnetic beads in 100 μL of 1× protein-RNA Binding buffer; prepare the RNA-protein binding reaction premix according to the table below (Table 1); collect the magnetic beads from the side of the magnetic separation rack, discard the supernatant, and add 100 μL of the RNA-protein binding reaction premix to the magnetic beads, and incubate at 4°C with shaking for 60 minutes. Dosage group: Incubate the protein lysate with the compound (Compound I, lead compound 10-3, or Compound A, 1 nM) at room temperature with shaking for 1 hour.

[0067] Table 1 Premix formula for RNA-protein binding reaction

[0068]

[0069]

[0070] Elution of RNA-protein complexes: Place the centrifuge tube on a magnetic separation rack, collect beads on the side, and aspirate the supernatant for analysis. Wash the beads twice with 100 μL of 1× Wash buffer, retaining the supernatant for analysis. Resuspend the beads in 50 μL of 1× Wash buffer, gently mix, and incubate at 37°C with shaking for 30 minutes. Place the centrifuge tube on a magnetic separation rack and retain the supernatant. Add an equal volume of 2× Loading Buffer (purchased from Solebold) to the supernatant from the final Elution Buffer step, mix thoroughly, and boil in a 95°C metal bath for 10-15 minutes. Detect the pulled-down PSF protein by Western blot.

[0071] 2. Results Analysis

[0072] according to Figure 4 It can be seen that compared with the blank control group, it was found that both formula (I) and compound A could inhibit the binding of lncRNA to PSF protein, and the inhibitory effect of compound I was significantly better than that of the lead compound 10-3 and compound A.

[0073] Example 5: Cell cycle detection

[0074] 1. Experimental Plan

[0075] Preparation of cell samples: When the growth rate was about 80%, HCT116 cells (Jinan Boshang Company) were seeded in a six-well plate. After the cells adhered to the wall, different compounds (Compound I, lead compound 10-3 or Compound A, 25μM) were added to each well and cultured in a cell culture incubator for 48h. The culture medium was removed and washed with PBS. 300μL of trypsin was added to each well for about 1min. The digestion was terminated and the cells were collected. The cells were centrifuged at 1000rpm for 3-5min and the supernatant was discarded. The cells were washed twice with 2mL of pre-cooled PBS and centrifuged again to discard the supernatant. The cells were resuspended in 250μL of cold PSB, 750μL of pre-cooled anhydrous ethanol was added dropwise, mixed gently, and placed at 4°C for fixation overnight.

[0076] Staining: Prepare the staining solution in the dark. After fixation, centrifuge the cells at 1000 rpm for 3-5 minutes, remove the fixative, rinse the cells with PBS, and centrifuge again to discard the supernatant. Add 500 μL of the prepared staining solution, mix gently, and incubate at 37°C in the dark for 30 minutes.

[0077] Flow cytometry: Red fluorescence was detected by flow cytometry at an excitation wavelength of 488 nm, and light scattering was detected simultaneously.

[0078] 3. Results Analysis

[0079] like Figure 5As shown, compared with the blank control group, the proportion of G0 / G1 phase cells in the compound represented by formula (I) decreased, and the proportion of G2 / M phase cells increased, which means that the drug-treated group can arrest cells in the G2 / M phase and affect the synthesis of RNA and protein.

[0080] Example 6: Western Blot

[0081] 1. Experimental Plan

[0082] Preparation of Cell Protein Samples: When HNSCC cells reached approximately 80% growth, they were seeded in six-well plates. After cells adhered, different compounds (Compound I, lead compound 10-3, or Compound A, 25 μM) were added to each well and cultured in a cell culture incubator for 48 hours. Cells were observed under a microscope. The culture medium from wells showing minimal changes in cell status was discarded, and the cells were rinsed once with 1 mL of PBS. Then, 150-250 μL of RIPA lysis buffer (PMSF was added to the lysis buffer several minutes beforehand to a final concentration of 1 mM) was added to each well. The cells were gently agitated to allow for thorough contact between the lysis buffer and the cells, and lysed on ice for 5-10 minutes. The lysed cells were scraped with a scraper, transferred to a centrifuge tube, and centrifuged at 12,000 rpm at 4°C for 5-10 minutes. The supernatant was retained. The culture medium from wells with significant cell death was retained in a centrifuge tube, the supernatant discarded, and RIPA lysis buffer (containing 1 mM PMSF) was added. The cells were gently mixed, lysed on ice, and centrifuged to obtain the supernatant. The protein concentration was determined using a BCA protein concentration assay kit. An equal volume of 2× protein loading buffer was added, mixed evenly, and boiled in a 95°C metal bath for 10-15 minutes. The sample was then stored in a -20°C refrigerator until ready for use.

[0083] Western blot was used to detect the expression level of the target protein: 20 μg of protein was loaded, the voltage was adjusted to 80 V, and the electrophoresis was terminated when the bromophenol blue just ran out of the bottom of the separation gel. The PAGE gel was then placed on a transfer membrane instrument (BioRad, USA), transferred at a constant current of 200 mA for 1 hour, blocked with 5% milk powder for 2 hours, and washed 3 times with TBST buffer, each time for 10 minutes. The primary antibody (p53 antibody, 1:5000) diluted in antibody diluent was added and incubated overnight at 4°C. After washing with TBST, the secondary antibody labeled with horseradish peroxidase (HRP-IgG, 1:4000) was added and incubated at room temperature for 2 hours. After washing with TBST, ECL developer was added and the gel was exposed and developed on a chemiluminescence imaging system (Thermo Fisher) and its grayscale value was analyzed using the gel image processing system (see attached figure). Figure 6 shown).

[0084] 4. Results Analysis

[0085] like Figure 6As shown, compared with the blank control group, the compound represented by formula (I), the lead compound 10-3 and compound A can all upregulate the expression of p53 protein, and the p53 protein expression level upregulated by compound 1 is significantly greater than the p53 protein expression levels upregulated by the lead compound 10-3 and compound A, which may be the reason for the above-mentioned cell cycle experimental results (the number of G0 / G1 phase cells is significantly reduced, and the number of G2 / M phase cells is significantly increased).

[0086] Example 7: In vivo animal experiment

[0087] 1. Experimental Methods

[0088] HNSCC cells (1×10 6 The HNSCC animal model was established by inoculating the mice subcutaneously in the forelimbs of 4-6 week-old male mice with 10-3 (0.5 μg / mouse). One week later, the mice were randomly divided into six groups: control group, compound 1 alone group, nedaplatin alone group, 10-3 + nedaplatin group, compound A + nedaplatin group, and compound 1 + nedaplatin group, with 5 mice in each group.

[0089] The compound 1 alone group was intraperitoneally injected with compound 1 twice a week (5 mg / kg each time).

[0090] Nedaplatin alone group: Nedaplatin was injected intraperitoneally twice a week (5 mg / kg each time).

[0091] 10-3 + Nedaplatin group: Compound 10-3 was intraperitoneally injected twice a week (5 mg / kg each time); Nedaplatin was intraperitoneally injected twice a week (5 mg / kg each time).

[0092] Compound A+nedaplatin group: Compound A was intraperitoneally injected twice a week (5 mg / kg each time); nedaplatin was intraperitoneally injected twice a week (5 mg / kg each time).

[0093] Compound 1 + Nedaplatin group: Compound 1 was intraperitoneally injected twice a week (5 mg / kg each time); Nedaplatin was intraperitoneally injected twice a week (5 mg / kg each time).

[0094] Control group: injected with the same dose of normal saline.

[0095] The tumor volume was measured with a vernier caliper every 3 days. After 21 days of administration, the mice were sacrificed and the tumors were removed.

[0096] 2. Results Analysis

[0097] Depend on Figure 7It can be seen that the combination of Compound 1 and the platinum antitumor agent nedaplatin can significantly inhibit tumor growth, resulting in a decrease in tumor volume and tumor weight. The tumor inhibition effect of the Compound 1 + nedaplatin group was better than that of the 10-3 + nedaplatin group and the Compound A + nedaplatin group. The tumor inhibition rate of the combined action of Compound 1 and nedaplatin was greater than the sum of the tumor inhibition rates of Compound 1 and nedaplatin, indicating that Compound 1 and the platinum antitumor agent exerted a synergistic effect.

Claims

1. An epigenetic drug, characterized in that it is A compound represented by formula (I) or a pharmaceutically acceptable salt thereof; （I）。 2. Use of the epigenetic drug according to claim 1 in the preparation of a platinum anti-tumor agent anticancer sensitization composition.

3. The use according to claim 2, characterized in that The platinum anti-tumor agent is at least one of cisplatin, carboplatin, nedaplatin, cycloplatin, oxaliplatin, and lobaplatin.

4. The use according to claim 2, characterized in that: The tumor targeted by the platinum antitumor agent is at least one of lung cancer, pancreatic cancer, prostate cancer, testicular cancer, ovarian cancer, colorectal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, germ cell cancer, and lymphoma.

5. An anticancer sensitization composition, characterized in that: It comprises a platinum antitumor agent and a compound represented by formula (I) according to claim 1.

6. The anticancer sensitization composition according to claim 5, characterized in that: The molar ratio of the platinum antitumor agent to the compound represented by formula (I) is 1:1-1:3.

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