Application of ginkgetin in enhancing VS4718 or ponatinib in resisting esophageal squamous cell carcinoma progress

Abstract

The invention provides an application of ginkgetin in enhancing VS4718 or ponatinib in resisting the progress of esophageal squamous cell carcinoma. It is found that ginkgo biflavone can enhance the growth and invasion inhibition effect of VS4718 or ponatinib on esophageal squamous carcinoma cells; ginkgo biflavone is used for enhancing the inhibition effect of VS4718 or ponatinib on glycolipid metabolism of tumor cells, and the ginkgo biflavone is respectively combined with VS4718 or ponatinib to generate a synergistic anti-cancer effect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions, and in particular to the application of ginkgo biflavonoids in enhancing the effect of VS4718 or ponatinib on preventing the progression of esophageal squamous cell carcinoma. Background Art

[0002] Esophageal squamous cell carcinoma (ESCC) is a solid tumor that seriously endangers human health worldwide and is also one of the most common and idiopathic cancers. With the improvement of diagnosis and treatment, the survival rate and survival status of ESCC patients have improved, but the prognosis is still not ideal. Discovering new diagnostic markers and treatment strategies is crucial in targeting ESCC.

[0003] Tyrosine kinases can regulate various malignant phenotypes of ESCC by mediating the transmission of signal pathways. Among them, the focal adhesion kinase (FAK) / Src signaling axis is an important signaling pathway that promotes the progression of ESCC. Several small molecule inhibitors targeting the FAK / Src axis have been developed, but their anticancer effects still need further study.

[0004] Small molecule monomer compounds of traditional Chinese medicine can synergistically inhibit tumor cell progression and reduce drug toxicity through multiple pathways and multiple targets. Therefore, the study of traditional Chinese medicine-assisted targeted drugs against ESCC has become the focus of current oncology research.

[0005] Ginkgetin is a biflavonoid from Ginkgo biloba. It is a flavonoid compound with anti-inflammatory and antioxidant biological effects. Its structure is as follows:

[0006]

[0007] Ginkgo biloba flavonoids have a wide range of biological activities, such as anti-inflammatory, anti-oxidation, and prevention of cardiovascular and cerebrovascular diseases. In recent years, it has also been reported that ginkgo biloba flavonoids can inhibit multiple malignant phenotypes of solid tumor cell lines, such as growth, invasion and metastasis, and have anti-cancer effects. However, there has been no research on the enhancement of the anti-cancer effects of ginkgo biloba flavonoids on FAK inhibitors and Src family kinase inhibitors. Summary of the invention

[0008] The present invention finds that ginkgo biloba flavonoids can enhance the effect of FAK inhibitors and Src family kinase inhibitors in resisting the progression of esophageal squamous cell carcinoma. When ginkgo biloba flavonoids are used in combination with FAK inhibitors or Src family kinase inhibitors, the drug combination can achieve a synergistic anti-cancer effect.

[0009] In a first aspect, the present invention provides a pharmaceutical composition comprising ginkgo biflavonoids or a pharmaceutically acceptable salt thereof and a FAK inhibitor or a Src family kinase inhibitor.

[0010] In a second aspect, the present invention further provides a kit comprising ginkgo biloba flavonoids or a pharmaceutically acceptable salt thereof and a FAK inhibitor or a Src family kinase inhibitor.

[0011] Preferably, the molar ratio of ginkgo biflavonoids or a pharmaceutically acceptable salt thereof to FAK inhibitor or Src family kinase inhibitor is 1-30:1, preferably 3-8:1, and more preferably 5:1.

[0012] Preferably, the FAK inhibitor includes VS4718 or a pharmaceutically acceptable salt thereof; and the Src family kinase inhibitor includes ponatinib or a pharmaceutically acceptable salt thereof.

[0013] In the present invention, the CAS registration number of the VS4718 is 1061353-68-1, and the chemical name is 2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide); the CAS registration number of ponatinib is 9 43319-70-8, the chemical name is 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]benzamide (3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]benzamide).

[0014] Preferably, the molar ratio of ginkgo biloba flavonoids or its pharmaceutically acceptable salt to VS4718 or its pharmaceutically acceptable salt is 0.5-15:1, preferably 1-6:1, more preferably 2:1; the molar ratio of ginkgo biloba flavonoids or its pharmaceutically acceptable salt to ponatinib or its pharmaceutically acceptable salt is 0.5-15:1, preferably 1-6:1, more preferably 2:1.

[0015] In a third aspect, the present invention also provides use of the pharmaceutical composition in preparing a drug for preventing the progression of esophageal squamous cell carcinoma.

[0016] In a fourth aspect, the present invention provides the use of ginkgo biloba biflavonoids or a pharmaceutically acceptable salt thereof in enhancing the effect of FAK inhibitors or Src family kinase inhibitors against the progression of esophageal squamous cell carcinoma.

[0017] In a fifth aspect, the present invention also provides the use of ginkgo biflavonoids or a pharmaceutically acceptable salt thereof in the preparation of a drug for enhancing the effect of a FAK inhibitor or a Src family kinase inhibitor against the progression of esophageal squamous cell carcinoma.

[0018] In the present invention, the anti-progression of esophageal squamous cell carcinoma includes inhibiting the growth of esophageal squamous cell carcinoma cells, inhibiting the invasion of esophageal squamous cell carcinoma cells in metastatic foci, inhibiting the sugar metabolism of esophageal squamous cell carcinoma cell lines, and inhibiting the fatty acid metabolism of esophageal squamous cell carcinoma cell lines.

[0019] In a preferred embodiment, the esophageal squamous cell carcinoma cells include esophageal squamous cell carcinoma cell line KYSE410, esophageal squamous cell carcinoma cell line KYSE450, and esophageal squamous cell carcinoma cell line KYSE510, and more preferably esophageal squamous cell carcinoma cell line KYSE450.

[0020] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include (by way of example only) sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines and tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dienylamines, trialnylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, monocyclic alkylamines, dicyclic alkylamines or tricyclic alkylamines, monoarylamines, diarylamines or triarylamines or salts of mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0021] In one embodiment, the medicament or pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier or excipient.

[0022] The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffers, and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and perfuming agents and the like.

[0023] The pharmaceutical composition or medicament of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, to the cheek, vaginally or through an implanted reservoir, preferably by oral administration or by injection. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intrawound and intracranial injection or infusion techniques.

[0024] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dibasic calcium phosphate) and / or: a) fillers or expanders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) wetting agents such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarder such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as clay and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0025] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics.

[0026] Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be prepared according to known techniques using appropriate dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. In addition, sterile fixed oils are usually used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or di-glycerides.

[0027] The dosage form of the pharmaceutical composition of the present invention or the medicine administered topically or percutaneously includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. Under aseptic conditions, the active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or required buffer. Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also included within the scope of the present invention.

[0028] In one embodiment, the ginkgo biflavonoids or its pharmaceutically acceptable salt and the FAK inhibitor or Src family kinase inhibitor in the pharmaceutical composition, kit or medicine of the present invention can be administered in the same or different pharmaceutical preparations. The pharmaceutical dosage forms of the ginkgo biflavonoids or its pharmaceutically acceptable salt and the FAK inhibitor or Src family kinase inhibitor can be the same or different. The ginkgo biflavonoids or its pharmaceutically acceptable salt and the FAK inhibitor or Src family kinase inhibitor can be administered simultaneously or sequentially.

[0029] In the medical uses described herein, the administration time, number of administrations and frequency of administration of ginkgo biloba biloba or its pharmaceutically acceptable salt and FAK inhibitor or Src family kinase inhibitor, etc., need to be determined according to the specific diagnosis results of the disease, which is within the technical scope mastered by those skilled in the art.

[0030] For example, when a treatment regimen for mice or rats is applied to humans, the effective doses of all drugs for humans can be converted by the effective doses of the drugs for mice or rats, which is also easy to achieve for ordinary technicians in this field.

[0031] The medicaments or pharmaceutical compositions of the present invention can be produced in a manner known to those skilled in the art, for example, by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0032] Beneficial effects:

[0033] The present invention provides the use of ginkgo biloba flavonoids to enhance VS4718 and ponatinib in the fight against the progression of esophageal squamous cell carcinoma. As evaluated by the MTS method and soft agar clone formation experiment, ginkgo biloba flavonoids can enhance the growth inhibition of esophageal squamous cell carcinoma cell KYSE450 mediated by VS4718 and ponatinib. As evaluated by the Transwell method, ginkgo biloba flavonoids can enhance the inhibition of esophageal squamous cell carcinoma cell invasion by VS4718 and ponatinib. Ginkgo biloba flavonoids significantly enhance the metabolism of esophageal squamous cell carcinoma cell line KYSE450 by VS4718 and ponatinib, including reducing the content of lactate, glucose and fatty acids in ESCC cells. Ginkgo biloba flavonoids are used in combination with VS4718 and ponatinib, respectively, to achieve a synergistic anti-esophageal squamous cell carcinoma effect, which is beneficial to improve the anti-tumor effect, thereby being able to improve the anti-cancer activity of FAK inhibitors and Src family kinase inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS Description of the drawings:

[0035] Figure 1 This is a schematic diagram of the results showing that the ginkgo biloba biloba flavonoids of Example 1 can enhance the growth inhibition of esophageal squamous cell carcinoma cell lines by VS4718 or ponatinib.

[0036] Figure 2 This is a schematic diagram of the results showing that the ginkgo biloba biloba flavonoids of Example 2 can enhance the ability of VS4718 or ponatinib to inhibit the invasion of esophageal squamous cell carcinoma cell lines.

[0037] Figure 3 This is a schematic diagram of the results of Example 3 showing that ginkgo biloba flavonoids enhance the glucose metabolism of VS4718 or ponatinib in inhibiting esophageal squamous cell carcinoma cell lines.

[0038] Figure 4 This is a schematic diagram of the results of Example 4 showing that ginkgo biloba flavonoids enhance the inhibition of fatty acid metabolism in esophageal squamous cell carcinoma cell lines by VS4718 or ponatinib.

[0039] In the above figures, *** represents P < 0.001. DETAILED DESCRIPTION

[0040] The preferred embodiments of the invention are described in detail below. The examples are provided to better illustrate the content of the invention, but the content of the invention is not limited to the examples. Non-essential improvements and adjustments to the implementation scheme according to the content of the invention still fall within the scope of the invention.

[0041] The experimental methods in the following examples are all conventional methods unless otherwise specified. If no specific techniques or conditions are specified in the examples, they are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. Specific implementation method:

[0043] Example 1: Ginkgo biloba flavonoids enhance the growth inhibitory effect of VS4718 or ponatinib on esophageal squamous cell carcinoma cell lines

[0044] 1. Cell Culture

[0045] The human esophageal squamous cell carcinoma cell line KYSE450 was placed in RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin in an incubator at 37°C and 5% CO2.

[0046] 2. Cell growth ability determination (MTS method)

[0047] KYSE450 cell line (culture density 3×10 3 After the cells were inoculated into a 96-well plate, Ginkgo biloba (1 μM), VS4718 (0.5 μM), Ponatinib (0.5 μM) or a combination thereof were added. After 72 hours, a 10% MTS solution was prepared in RPMI 1640 medium, added to the 96-well plate and incubated for 2 hours. The absorbance was measured at 490 nm using a microplate reader.

[0048] 3. Cell growth ability determination (soft agar colony formation experiment)

[0049] After preparing the lower agarose layer in the 96-well plate, the plate was left to stand at 4°C for 20 minutes. Then, the upper agarose layer containing the KYSE450 cell line was prepared. After the preparation of the upper and lower agarose gels, a combination of Ginkgo biloba (1 μM) and VS4718 (0.5 μM) or Ponatinib (0.5 μM) was added to the upper layer. After incubation for 8 days, the color working solution was added, incubated at 37°C for 4 hours, and the absorbance value was measured at 450 nm using an ELISA reader.

[0050] Compare with Figure 1 The results showed that ginkgo biloba flavonoids could enhance the growth inhibition of ESCC cell lines by VS4718 or ponatinib.

[0051] The Jin Zhengjun Q value judgment method was used to evaluate the synergistic effect of the combination of ginkgo biloba flavonoids and VS4718 or ponatinib in inhibiting tumor growth. The Q value was calculated using the following formula: Q = E a+b / (E a +E b -E a ×E b ). a+b is the inhibition rate of the drug combination, E a and E b It is the inhibition rate of drug treatment when administered alone. Q<0.85 indicates antagonism, 0.85≤Q<1.15 indicates additive effect, and Q≥1.15 indicates synergistic effect.

[0052] After calculation, the Q value for the growth inhibition effect mediated by the combination of ginkgo biloba flavonoids and VS4718 was 1.25; the Q value for the growth inhibition effect mediated by the combination of ginkgo biloba flavonoids and ponatinib was 1.22.

[0053] For the non-anchorage-dependent growth inhibitory effect mediated by the combination of Ginkgo biloba flavonoids and VS4718, the Q value was 1.31; for the non-anchorage-dependent growth inhibitory effect mediated by the combination of Ginkgo biloba flavonoids and Ponatinib, the Q value was 1.25.

[0054] Example 2: Ginkgo biloba flavonoids enhance the inhibitory effect of VS4718 or ponatinib on esophageal squamous cell carcinoma cell line invasion

[0055] Cell invasion ability detection:

[0056] The Tranwell system (8 μm pore size) was used to observe the ability of Ginkgo biloba flavonoids to enhance the VS4718 and ponatinib anti-ESCC cell invasion. 100 μL of matrix gel was added to the upper chamber of the transwell chamber and incubated at 37°C for 1 hour to solidify the matrix gel. The prepared KYSE450 cell line was inoculated in the upper chamber of the transwell chamber, and 800 μL of RPMI 1640 medium containing 20% ​​fetal bovine serum was added to the lower chamber, and Ginkgo biloba flavonoids (1 μM), VS4718 (0.5 μM), ponatinib (0.5 μM) or their combination were added, and the transwell chamber was placed in an incubator and incubated for 24 hours. After removal, the non-invaded KYSE450 cells in the upper chamber were wiped clean with a cotton swab, and the invaded KYSE450 cells in the lower chamber were separated by dissociation solution, and the separated cells were added with dyes. After staining, the invasion cell rate was calculated by an ELISA instrument.

[0057] Compare with Figure 2 The results showed that ginkgo biloba flavonoids could enhance the invasion of VS4718 or ponatinib in esophageal squamous cell carcinoma cell lines.

[0058] After calculation, the Q value for the invasion inhibition effect mediated by ginkgo biloba flavonoids combined with VS4718 was 1.3; the Q value for the invasion inhibition effect mediated by ginkgo biloba flavonoids combined with ponatinib was 1.27.

[0059] Example 3: Ginkgo biloba flavonoids enhance the glucose metabolism inhibition effect of VS4718 or ponatinib on esophageal squamous cell carcinoma cell lines

[0060] The KYSE450 cell line was inoculated in a 6-well plate. After the cells adhered to the wall, Ginkgo biloba (1 μM), VS4718 (0.5 μM), Ponatinib (0.5 μM) or a combination thereof were added. After 24 hours, the conditioned medium was collected, and the conditioned medium under different treatments was incubated with different reagents according to the instructions of the reagent manual using a lactic acid detection kit (Nanjing Jiancheng Bioengineering Research Institute Co., Ltd., item number: A019-3-1). The absorbance was displayed by an ELISA instrument and the lactic acid content was determined. The glucose detection kit (Biyuntian Biotechnology Research Institute Co., Ltd., item number: S0201S) was used to incubate the conditioned medium under different treatments with different reagents according to the instructions of the reagent manual, and the absorbance was displayed by an ELISA instrument and the glucose content was determined.

[0061] Compare with Figure 3 The results showed that ginkgo biloba flavonoids could enhance the glucose metabolism of esophageal squamous cell carcinoma cell lines inhibited by VS4718 or ponatinib.

[0062] After calculation, the Q value for the lactate inhibition effect mediated by the combination of Ginkgo biloba flavonoids and VS4718 was 1.32; the Q value for the lactate inhibition effect mediated by the combination of Ginkgo biloba flavonoids and Ponatinib was 1.34. The Q value for the glucose inhibition effect mediated by the combination of Ginkgo biloba flavonoids and VS4718 was 1.31; the Q value for the glucose inhibition effect mediated by the combination of Ginkgo biloba flavonoids and Ponatinib was 1.36.

[0063] Example 4: Ginkgo biloba flavonoids enhance the inhibitory effect of VS4718 or ponatinib on fatty acid metabolism in esophageal squamous cell carcinoma cell lines

[0064] KYSE450 cell lines were inoculated in 6-well plates, and after the cells adhered to the wall, Ginkgo biloba (1 μM), VS4718 (0.5 μM), Ponatinib (0.5 μM) or their combination were added. After 24 hours, the conditioned medium was collected and incubated with different reagents according to the instructions of the reagent manual using a fatty acid detection kit (Nanjing Jiancheng Bioengineering Research Institute Co., Ltd., item number: A042-2-1). The absorbance was displayed by an ELISA instrument and the fatty acid content in the conditioned medium was determined.

[0065] Compare with Figure 4The results showed that ginkgo biloba flavonoids could enhance the fatty acid metabolism of esophageal squamous cell carcinoma cell lines inhibited by VS4718 or ponatinib.

[0066] After calculation, the Q value for the fatty acid inhibition effect mediated by the combination of ginkgo biloba flavonoids and VS4718 was 1.26; the Q value for the fatty acid inhibition effect mediated by the combination of ginkgo biloba flavonoids and ponatinib was 1.22.

[0067] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made in form and details without departing from the scope defined by the claims of the present invention.

Claims

1. A pharmaceutical composition comprising ginkgo biflavonoids or a pharmaceutically acceptable salt thereof and a FAK inhibitor or a Src family kinase inhibitor.

2. The pharmaceutical composition according to claim 1, characterized in that The molar ratio of ginkgo biloba flavonoids or a pharmaceutically acceptable salt thereof to the FAK inhibitor or the Src family kinase inhibitor is 0.5-15:

1.

3. The pharmaceutical composition according to claim 1, characterized in that The molar ratio of ginkgo biloba flavonoids or a pharmaceutically acceptable salt thereof to the FAK inhibitor or the Src family kinase inhibitor is 1-6:

1.

4. The pharmaceutical composition according to claim 1, characterized in that The FAK inhibitor includes VS4718 or a pharmaceutically acceptable salt thereof; the Src family kinase inhibitor includes ponatinib or a pharmaceutically acceptable salt thereof.

5. A kit comprising ginkgo biloba flavonoids or a pharmaceutically acceptable salt thereof and a FAK inhibitor or a Src family kinase inhibitor.

6. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a drug for preventing the progression of esophageal squamous cell carcinoma.

7. Use of ginkgo biloba flavonoids or pharmaceutically acceptable salts thereof in enhancing the effect of FAK inhibitors or Src family kinase inhibitors against the progression of esophageal squamous cell carcinoma.

8. Use of ginkgo biflavonoids or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the effect of a FAK inhibitor or a Src family kinase inhibitor against the progression of esophageal squamous cell carcinoma.

9. The use according to any one of claims 6 to 8, characterized in that: The anti-progression of esophageal squamous cell carcinoma comprises inhibiting the growth of esophageal squamous cell carcinoma cells, inhibiting the invasion of esophageal squamous cell carcinoma cells in metastatic foci, inhibiting the sugar metabolism of esophageal squamous cell carcinoma cell lines, and inhibiting the fatty acid metabolism of esophageal squamous cell carcinoma cell lines.

10. The use according to claim 9, characterized in that: The esophageal squamous cell carcinoma cells include esophageal squamous cell carcinoma cell line KYSE410, esophageal squamous cell carcinoma cell line KYSE450, and esophageal squamous cell carcinoma cell line KYSE510.

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