Kidney-type glutaminase inhibitor and application of drug combination of kidney-type glutaminase inhibitor

Abstract

The invention relates to a kidney-type glutaminase inhibitor and application of drug combination of the kidney-type glutaminase inhibitor. A specific KGA inhibitor compound is analyzed, screened and identified in a known compound library through a molecular docking technology, and the compound has a good KGA inhibition characteristic and can remarkably improve the effect of treating fibrosarcoma after being used in combination with specific genistein. After the two are prepared into the medicine box, the medicine box has an excellent application prospect.

Description

Technical Field

[0001] The present application relates to the field of biopharmaceuticals, and specifically to the use of renal glutaminase inhibitors and their combined use. Background Art

[0002] The kidney-type glutaminase GLS is encoded by the GLS gene located on chromosome 2 in humans and has different splice variants. The longest one is called kidney glutaminase (KGA). The human KGA sequence was deduced from sequencing of a large number of isolated cDNAs, and more targeted studies have been conducted on the mouse and porcine KGA analogs that have been discovered. The GLS gene has been studied and found to consist of 19 exons and is over 82 kb in length. Exons 1-15 are spliced ​​to GAC, and exons 1-14 and 16-19 are spliced ​​to KGA. The GAM mRNA contains 2-3 introns, which diverge from GAC / KGA starting at residue 162. The C-terminal sequence of GAM is "VSFYIFLS" and is encoded by introns 2-3. Introns are very rare as alternative splicing forms in mammalian cells, so it is not certain whether GAM is the result of a genetic defect in the cell from which the cDNA was isolated.

[0003] The role of renal glutaminase in cancer has always been a focus of research. The Cancer Genome Atlas (TCGA) pan-cancer gene expression data showed that GLS is highly expressed in acute myeloid leukemia, adrenocortical carcinoma, triple-negative breast cancer, colorectal cancer, renal clear or papillary cell carcinoma, lung adenocarcinoma, melanoma, mesothelioma, pancreatic cancer, sarcoma and thyroid cancer. Among them, small molecule inhibitors and gene silencing experiments found that GLS is essential for the growth of acute myeloid leukemia, breast cancer, colorectal cancer, kidney cancer, lung cancer, melanoma and pancreatic cancer cells. Although TCGA data showed that glioblastoma cell lines have relatively low GLS expression, they are still very sensitive to glutaminase inhibitors in vitro. These results indicate that GLS is essential for the growth of various cancer cell lines and that inhibition of this enzyme is a potentially valuable therapeutic strategy.

[0004] In the 80 years since the discovery of glutaminase, the only chemical inhibitor that has attracted attention is DON (6-diazo-5-oxo-1-isoleucine). DON is a glutamine mimetic that binds irreversibly to the catalytic serine of both glutaminase isozymes. Although other small molecules have been used to inhibit GLS (especially membrane-impermeable molecules used to determine subcellular localization), DON has been the most widely used inhibitor in the past decade. However, DON's application is limited by its broad target and severe toxicity. In 2007, another inhibitor of GLS, BPTES, was discovered. BPTES is a long, highly flexible and C2-symmetric molecule that binds to GLS in a 1:2 ratio and is located at the binding interface of the dimer. The affinity of BPTES for GLS is about 1000 times that of LGA. However, to date, the only GLS enzymes used for research are recombinant mutant GLS enzymes, and BPTES has a binding site similar to that of LGA. Since the crystal structure of BPTES and GLS complex was reported, BPTES has been a hot topic of research, with the focus mainly on increasing inhibitor affinity and improving its drug properties.

[0005] In addition, in a new study, researchers from research institutions such as the University of Tokyo, Keio University and Kyushu University in Japan found that inhibiting kidney-type glutaminase (KGA)-dependent glutaminolysis in mice can eliminate senescent cells. Specifically, RNA interference (RNAi) was used to find enzymes required for the survival of senescent cells and subsequently induce their death. This study involved using RNA interference to find enzymes required for the survival of senescent cells. This prompted them to take a closer look at glutamine metabolism, especially glutaminase 1 (GLS1). Tests showed that it was essential for the survival of senescent cells. Then, these researchers inhibited the glutaminase 1 pathway in the test mice. After giving these changes time to take effect, inhibiting this pathway led to the death of senescent cells. In the long run, this also reduces age-related organ problems and reduces obesity-related health problems.

[0006] However, at present, there are not enough studies on inhibitors of renal glutaminase GLS, and there are not enough options available. Summary of the invention

[0007] In one aspect, the present invention provides a specific KGA inhibitor.

[0008] The KGA inhibitor is a compound.

[0009] The structural formula of the KGA inhibitor compound of the present invention is as follows:

[0010]

[0011] The compound can also be synthesized according to the prior art CN102030700B.

[0012] Furthermore, the present invention provides a pharmaceutical composition for treating fibrosarcoma tumors, wherein the pharmaceutical composition comprises the KGA inhibitor compound of the present invention and pharmaceutical excipients.

[0013] Further, the pharmaceutical excipients can be excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0014] Furthermore, substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose. sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; 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; glycol compounds such as propylene glycol and polyethylene 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, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0015] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; 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; glycol compounds such as propylene glycol and polyethylene 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, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0016] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0017] The therapeutically effective amount of the composition of the present invention may vary according to a variety of factors, such as the method of administration, the target site, the patient's condition, etc. Therefore, when the composition of the present invention is used in the human body, the dosage should be determined as an appropriate amount that takes into account both safety and effectiveness. The amount used in the human body can also be estimated by the effective dose determined by animal experiments. Things to consider when determining the effective amount are described in the following documents, such as Hardman and Limbird, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition (2001), Pergamon Press; and EWMartin, Remington's Pharmaceutical Sciences, 18th Edition (1990), Mack Publishing Company.

[0018] The composition of the present invention may include carriers, diluents, excipients and mixtures of two or more of the above substances traditionally used for biological preparations. Pharmaceutically acceptable carriers may be any carrier suitable for in vivo delivery of the composition without particular limitation. For example, a mixture of compounds described in Merck Index (13th edition, Merck & Co. Inc.), saline solution, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of the above components may be used, and other conventional additives (such as antioxidants, buffer solutions, bacteristats, etc.) may be added if necessary. In addition, diluents, dispersants, surfactants, binders and lubricants may be added to prepare injections (such as aqueous solutions, suspensions, emulsions), pills, capsules, granules or tablets. In addition, compositions may be prepared according to the appropriate methods in the art or the methods disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th edition, 1990) according to each disease or component.

[0019] The composition of the present invention may further comprise one or more active ingredients having the same or similar functions. Relative to the total weight of the composition, the composition of the present invention may comprise about 0.0001 wt% to about 10 wt%, preferably about 0.001 wt% to about 1 wt%.

[0020] Depending on the intended method, the composition of the present invention can be administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) or orally. The dosage can vary according to body weight, age, sex, health status, diet of a particular patient, administration period, administration method, clearance rate, and severity of the disease. The daily dosage of the composition of the present invention is about 0.0001 mg / mL to about 10 mg / mL, preferably about 0.0001 mg / mL to about 5 mg / mL, and more preferably once a day or several times a day in a divided manner to administer the composition of the daily dosage.

[0021] Furthermore, the present invention also provides a drug kit for treating fibrosarcoma tumors, wherein the drug kit comprises the KGA inhibitor compound of the present invention and genistein.

[0022] Furthermore, the dosage ratio of the two drugs is 1:1-1:5, more preferably 1:2.

[0023] Furthermore, the present invention also provides the use of KGA inhibitor compounds and genistein in preparing a drug kit for treating fibrosarcoma tumors.

[0024] Furthermore, the dosage of the medicine kit is a pharmaceutically effective amount.

[0025] The pharmaceutically effective amount can be the total amount of the two, but is not limited to, about 0.00001 mg / kg to about 10 mg / kg, preferably about 0.0001 mg / kg to about 1 mg / kg. The dosage can vary according to body weight, age, sex, health status, diet of a particular patient, administration period, administration method, clearance rate, and severity of the disease.

[0026] The subject may be a vertebrate, preferably a mammal, more preferably an experimental animal (such as rats, rabbits, guinea pigs, hamsters, dogs and cats), and most preferably anthropoid apes (such as chimpanzees and gorillas). The administration method may be oral administration or parenteral administration. For parenteral administration, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, epidural injection, intracerebral blood vessel injection or intrathoracic injection may be selected.

[0027] Furthermore, based on the mechanism of the present invention, the medicine kit can also be used for the treatment of other cancers.

[0028] The term "cancer" as used herein refers to solid tumors and hematological tumors selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer (i.e., including colon cancer and rectal cancer), pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, hematological malignancies (e.g., leukemia), melanoma and sarcoma. More particularly preferred cancers are selected from the group consisting of hematological malignancies, prostate cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, melanoma and lung cancer. In a particularly preferred embodiment, the cancer is acute myeloid leukemia (AML) or prostate cancer.

[0029] Further, the drug in the kit is a solid dispersion. Solid dispersions, particularly MBP and / or spray-dried products obtainable according to the provided method, can be used in various forms of administering water-insoluble drugs (e.g., compound A), particularly for oral dosage forms. Exemplary dosage forms include powders or granules that can be dried or reconstituted by adding water to form a paste, slurry, suspension, or solution for oral ingestion; tablets, capsules, or pills. Various additives can be mixed, ground, or granulated with a solid dispersion as described in the present invention to form a material suitable for the above dosage form. Potentially beneficial additives can generally fall into the following categories: other matrix materials or diluents, surfactants, drug complexing agents or solubilizers, fillers, disintegrants, adhesives, lubricants, and pH modifiers (e.g., acids, bases, or buffers). Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium pyrophosphate, and starch. Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include polyethylene glycol, caffeine, xanthene, gentisic acid and cyclodextrin. Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose and cross-linked sodium carboxymethylcellulose. Examples of binders include methylcellulose, microcrystalline cellulose, starch and gums such as guar gum and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, etc.; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, etc., and buffers generally comprising a mixture of an acid and a salt of the acid. At least one effect of including this pH modifier is to control the dissolution rate of the drug, the matrix polymer or both, thereby controlling the local drug concentration during dissolution.

[0030] Beneficial Effects

[0031] The invention obtains a specific KGA inhibitor compound by analyzing, screening and identifying in a known compound library through molecular docking technology, and the compound has good KGA inhibition characteristics.

[0032] Combination therapy is a common and effective form of treatment for tumors, but it is not easy to choose which drug to combine with.

[0033] The inventors have identified dozens of drug combinations and accidentally discovered that the combination of the compound and a specific genistein can significantly improve the effect of treating fibrosarcoma tumors. When used with other common drugs such as paclitaxel, the synergistic effect is not significant.

[0034] The compound of the present invention has good safety, and the preparation method is also mature and known in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Tumor inhibition effect of each treatment group DETAILED DESCRIPTION

[0036] The specific embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although the specific embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided in order to enable a more thorough understanding of the present invention and to enable the scope of the present invention to be fully communicated to those skilled in the art.

[0037] Example 1 Screening for human KGA recombinant protein inhibitors

[0038] The amino acid sequence of the functional active region of human KGA is as follows

[0039] IPDFMSFTSH IDELYESAKK QSGGKVADYIPQLAKFSPDL WGVSVCTVDG QRHSTGDTKV

[0040] PFCLQSCVKP LKYAIAVNDL GTEYVHRYVG KEPSGLRFNK LFLNEDDKPH NPMVNAGAIV

[0041] VTSLIKQGVN NAEKFDYVMQ FLNKMAGNEY VGFSNATFQS ERESGDRNFA IGYYLKEKKC

[0042] FPEGTDMVGI LDFYFQLCSI EVTCESASVM AATLANGGFCPITGERVLSP EAVRNTLSLM

[0043] HSCGMYDFSG QFAFHVGLPA KSGVAGGILL VVPNVMGMMC WSPPLDKMGN SVKGIHFCHD

[0044] LVSLCNFHNY DNL; Detai Bio was commissioned to perform Pichia pastoris recombinant expression to obtain the functional active protein KGA, which was identified as an active recombinant protein by SDS-PAGE and human kidney-type glutaminase ELISA kit (catalog number 2H-KMLJh315182, brand Camilo camilo), and the protein concentration was adjusted to 1 mg / mL for use.

[0045] The KGA inhibitor compound (Formula 1) obtained by molecular docking technology screening was adjusted to a final concentration of 0-100 μM in the enzyme reaction system. Specifically, it was made into: K2PO4 0.15M,

[0046] Tris-Acetate pH 8.65 0.00 mM, bovine serum albumin BSA 0.10 mg / mL, EDTA 0.25 mM, DTT 1.00 mM, NAD 4.00 mM, glutamine 0-20 mM, glutamate dehydrogenase GDH 1 unit, KGA

[0047] 1.00 μM, compound 0-100 μM.

[0048] The reaction system without enzyme KGA and compound was prepared according to the above concentrations. The reaction group without compound was used as the blank group. Protein KGA was added in the last step. The change of OD value at 340nm of the reaction system within 10min was measured at 37℃. The final volume of the enzyme reaction system was 100.00μL, and 3 replicates were performed for each reaction. The reaction system without proteinase KGA and compound was prepared according to the same steps as above. The compound and enzyme KGA were co-incubated at 37℃ for 10min, and then the enzyme reaction system was added to start the reaction. The final volume was 100.00μL, and the change of OD value within 10min was measured. There were 3 replicates for each reaction condition. The inhibition OD value of the compound on the enzyme reaction system was measured. BPTES was used as a positive control compound, and its inhibitory activity on KGA was measured by the same steps. The IC50 value of the compound on KGA was calculated. The results are shown in Table 1.

[0049] Table 1 IC50 values ​​of compounds against KGA

[0050] Compound Type IC50(μM) KGA inhibitor compound (Formula 1) 2.03±0.12 BPTES positive control 8.67±0.56

[0051] It can be seen from Table 1 that the KGA inhibitor compound (Formula 1) of the present invention has good inhibitory activity against KGA.

[0052] Example 2 Cytotoxicity assay of KGA inhibitor compound (Formula 1)

[0053] Human fibrosarcoma cells HT1080 were purchased from Yun-Clone (Beijing) Biotechnology Co., Ltd., model YKLHT-1080. The frozen cells in the liquid nitrogen tank were taken out, thawed quickly in a 37°C water bath, transferred to a 10 cm cell culture dish, and 10 mL of culture medium containing 10% FBS was added. The cells were cultured at 37°C and 5% CO2 for 4 h. After 4 h, the supernatant and non-adherent cells were aspirated and discarded. The cells were rinsed once with isotonic FBS phosphate buffer, discarded, and 10 mL of cell culture medium containing 10% FBS was added. When the cell density reached about 80%, the cells were digested with trypsin and counted. The cells were diluted to a density of 50,000 / mL with a culture medium containing 10% FBS, and added to a 96-well plate (100.00 μL of FBS was added to the outermost circle of the 96-well plate) with a spray gun, and cultured in a cell culture incubator for 12 h. 5) The compound was added with a cell culture medium (containing 10 % FBS) was diluted to a concentration gradient of 200.00μM, 100.00μM, 50.00μM, 25.00μM, 12.50μM, 6.25μM, 3.12μM, 1.56μM, and 0.78μM; the cell culture medium in the 96-well plate was sucked out with a discharge gun (try to suck it thoroughly), and the culture medium containing the compound was added respectively, with 3 replicates for each concentration, and cultured in a cell culture incubator at 37°C for 48h; CCK-8 solution was added to the cell culture medium without FBS to make the final concentration of CCK-8 10%; the cell culture medium in the 96-well plate was sucked out, 100.00μL of 10% CCK-8 cell culture solution was added, and cultured at 37°C for 30min; the OD value of each well was measured at a wavelength of 450nm, and the IC50 value of cell proliferation inhibition was calculated by GraphPad Prism 5.0. BPTES was used as a control. The results are shown in Table 2.

[0054] Table 2 IC50 values ​​of compounds against tumor cells HT1080

[0055] Compound Type IC50(μM) KGA inhibitor compound (Formula 1) 5.13±0.34 BPTES positive control 48.17±0.76

[0056] It can be seen from Table 2 that the KGA inhibitor compound (Formula 1) of the present invention has a significantly higher inhibitory activity on tumor cell proliferation than the reported positive control compound BPTES, and has a better activity in inhibiting tumor cells.

[0057] Example 3 Verification of the therapeutic effects of the compounds and their combination

[0058] Balb / C nude mice were provided by Beijing Weitonglihua Experimental Animal Co., Ltd.

[0059] Human fibrosarcoma HT1080 cell line in logarithmic growth phase was digested with 0.25% trypsin at room temperature, centrifuged to remove supernatant, washed twice with serum-free corresponding culture medium, counted cells, adjusted cell density, and prepared to about 5×1010 / L cell suspension. Take 0.2 ml of the prepared cell suspension and inoculate it subcutaneously in the right axilla of Balb / C nude mice. When the tumor volume reaches 100 mm 3 Around 2 hours, the animals were divided into groups and dosed.

[0060] The mice with human fibrosarcoma that were successfully inoculated were randomly divided into a model control group, a high-, medium-, and low-dose compound group, a positive control group, a combined administration group, and a genistein monotherapy group. The compound dosage was 2 mg / kg / 2d, 1 mg / kg / 2d, and 0.5 mg / kg / 2d. The drug was administered twice a week for 3 consecutive weeks by intraperitoneal injection. The control group was administered with the same compound, and the cyclophosphamide dosage was 2 mg / kg / 2d, administered twice a week, and administered intraperitoneally for 3 consecutive weeks. The combined administration group was a compound combined with genistein (purchased from Sigma), in which the compound dosage was 1 mg / kg / 2d, and genistein was 2 mg / kg / 2d, administered twice a week, and administered intraperitoneally for 3 consecutive weeks. The genistein monotherapy group was genistein at 2 mg / kg / 2d, administered twice a week, and administered intraperitoneally for 3 consecutive weeks. The model group was injected with normal saline. The animals in each group were killed 24 hours after the last administration, and the tumors were removed and the tumor weight was measured. The average tumor weight and tumor inhibition rate of each group were calculated. Tumor inhibition rate (%) = (average tumor weight of the control group - average tumor weight of the drug group) / average tumor weight of the control group * 100%. Figure 1 shown.

[0061] from Figure 1 It can be seen that, compared with the model group, each treatment group has a significant tumor inhibition effect (P<0.01). And from the dosage of the compound, as the dosage increases, the tumor inhibition rate is gradually improved. And the therapeutic effect of the compound is better than that of the positive control group. The combination of the compound of the present invention and the genistein drug obtained by screening has a significant synergistic therapeutic effect, and the tumor inhibition rate reaches (98.14±2.92)%, which is much better than the drugs in the prior art and has a good therapeutic effect.

[0062] Before the mice in each treatment group were killed, the mice were tested for no obvious toxic side effects. After the mice were killed, the livers were taken to test the corresponding enzyme activity indicators, and there were no obvious liver poisoning symptoms, indicating that the compound has good safety.

[0063] Finally, it should be noted that the above 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 with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

[0064] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. Although embodiments of the present invention have been shown and described, those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to these embodiments without departing from the principles and purpose of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims

1. Use of a KGA inhibitor compound and genistein in preparing a drug kit for treating fibrosarcoma tumors, wherein the KGA inhibitor compound has the following structural formula:

2. The use according to claim 1, characterized in that The dosage ratio of the KGA inhibitor compound to genistein in the medicine kit is 1:

2.

3. The use according to claim 1, characterized in that The fibrosarcoma tumors described were caused by HT1080.

4. Use of a KGA inhibitor compound in the preparation of a drug for treating fibrosarcoma tumors, wherein the KGA inhibitor compound has the following structural formula:

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