Use of small-molecule reactivator compound in preparation of Anti-tumor drug

Abstract

Use of a small-molecule reactivator compound in the preparation of an anti-tumor drug. The small-molecule reactivator compound is a compound of formula I or a pharmaceutically acceptable salt thereof.

Description

Use of small molecule reactivator compounds in the preparation of therapeutic antitumor drugs

[0001] This application claims priority to an earlier application filed on December 26, 2024, with China National Intellectual Property Administration, patent application number 202411942205.1, entitled "Use of a small molecule reactivator compound in the preparation of a therapeutic antitumor drug"; the entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical applications, specifically relating to the use of a small molecule reactivator compound in the preparation of antitumor drugs. Background Technology

[0003] Tumors are a collection of related diseases characterized by the uncontrolled proliferation of tumor cells and the potential for metastasis throughout the body. TP53, a well-known tumor suppressor gene, is also one of the most frequently mutated genes in human cancers, with p53 mutations present in most malignant tumors. Among these, the oncogenic p53 Y220C mutant exhibits a particularly suitable structure for the development of small molecule stabilizers. The Tyr220 mutation to Cys forms a narrow hydrophobic cleft on the p53 DBD surface, thereby reducing its thermal stability by approximately 4 kcal / mol. Wild-type p53 is moderately stable, melting and denaturing at 44°C, while the Y220C mutant protein rapidly unfolds and denatures from its folded state at physiological body temperatures, effectively eliminating the tumor suppressor signal of wild-type p53 and driving tumorigenesis. Importantly, the hydrophobic cleft caused by the Y220C mutation is located away from the p53 protein surface involved in DNA recognition or protein-protein interactions, thus allowing for the development of small molecule drugs without interfering with its binding to natural DNA substrates. The Y220C mutant is a temperature-sensitive mutant that binds to DNA at lower temperatures and denatures at body temperature. When a small molecule compound selectively binds to the p53-Y220C mutant, the compound can stabilize the Y220C mutant, reducing the likelihood of p53 protein denaturation at body temperature, transforming p53 from its unfolded state to its folded state, and restoring the wild-type conformation and transcriptional activity of p53.

[0004] Therefore, developing small molecule reactivator compounds that can bind well to Y220C mutants, better restore the structure and transcriptional activity of wild-type p53, and more effectively inhibit tumors is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0005] To address the aforementioned technical problems, the present invention provides the use of at least one of a compound of formula I and a pharmaceutically acceptable salt of a compound of formula I in the preparation of a medicine;

[0006] Ra and Re may be the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl.

[0007] According to embodiments of the present invention, Ra and Re are independently selected from H, F, Cl, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, isopropoxy, or propoxy.

[0008] According to an exemplary embodiment of the present invention, the compound of formula I has the following structure:

[0009] According to embodiments of the present invention, the pharmaceutically acceptable salt may be an organic salt and / or an inorganic salt of a compound of formula I, for example, the organic salt is selected from at least one of methanesulfonate, lactate, maleate, malate, tartrate, ethylsulfonate, malonate and oxalate, and the inorganic salt is selected from at least one of hydrochloride, phosphate and sulfate.

[0010] According to embodiments of the present invention, the compound of formula I and / or a pharmaceutically acceptable salt of the compound of formula I may be its amorphous or polymorphic form.

[0011] According to an embodiment of the present invention, the drug is used to treat tumors carrying the p53-Y220C mutant; for example, it is used to treat solid tumors carrying the p53-Y220C mutant.

[0012] According to an embodiment of the present invention, the drug is used to treat solid tumors carrying the TP53 Y220C mutant.

[0013] According to an embodiment of the present invention, the drug is used to treat locally advanced or metastatic solid tumors carrying the TP53 Y220C mutant.

[0014] According to embodiments of the present invention, the drug is used to treat gastric cancer, lung cancer (such as non-small cell lung cancer), endometrial cancer, pancreatic cancer, liver cancer, oral cancer, breast cancer, and / or ovarian cancer.

[0015] According to an embodiment of the present invention, the tumor carrying the p53-Y220C mutant is a solid tumor carrying the TP53 Y220C mutant.

[0016] According to an embodiment of the present invention, the solid tumor carrying the TP53 Y220C mutant is a locally advanced or metastatic solid tumor carrying the TP53 Y220C mutant.

[0017] According to embodiments of the present invention, the solid tumors carrying the TP53-Y220C mutant include, but are not limited to, gastric cancer, lung cancer (such as non-small cell lung cancer), endometrial cancer, pancreatic cancer, liver cancer, oral cancer, breast cancer and / or ovarian cancer.

[0018] According to embodiments of the present invention, the drug may further comprise pharmaceutically acceptable excipients, such as carriers or excipients. For example, pharmaceutically acceptable excipients are selected from at least one of the following: fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, humectants, pH adjusters, solubilizers or cosolvents, osmotic pressure regulators, etc.

[0019] According to embodiments of the present invention, the routes of administration of the drug include, but are not limited to, intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, and in situ administration to the tumor.

[0020] According to embodiments of the present invention, the drug is preferably a pharmaceutical preparation, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, or concentrated solutions for injection), suppositories, inhalers, or sprays.

[0021] According to one embodiment of the present invention, the drug is a single-dose formulation or a multi-dose formulation, wherein the multi-dose formulation comprises more than one unit package, for example, consisting of 2 to 10 unit packages, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 unit packages. Wherein, each unit package contains the same amount of the compound of formula I and pharmaceutically acceptable salts of the compound of formula I, or at least two unit packages contain different amounts of the compound of formula I and pharmaceutically acceptable salts of the compound of formula I.

[0022] According to embodiments of the present invention, the medicament may also contain one or more therapeutic agents, used in combination with a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I.

[0023] The present invention also provides a treatment method for tumors carrying the p53-Y220C mutant, comprising administering a therapeutically effective amount of the drug to a patient;

[0024] Preferably, the tumor carrying the p53-Y220C mutant has the limitations shown above.

[0025] According to an embodiment of the present invention, the tumor carrying the p53-Y220C mutant is a solid tumor carrying the TP53 Y220C mutant.

[0026] According to an embodiment of the present invention, the tumor carrying the TP53 Y220C mutant is a locally advanced or metastatic solid tumor carrying the TP53 Y220C mutant.

[0027] According to embodiments of the present invention, the tumors carrying the p53-Y220C mutant include, but are not limited to, gastric cancer, lung cancer (such as non-small cell lung cancer), endometrial cancer, pancreatic cancer, liver cancer, oral cancer, breast cancer and / or ovarian cancer.

[0028] Terminology Definitions and Explanations

[0029] Unless otherwise stated, the definitions of terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations shall fall within the scope of this application specification.

[0030] Term "C" 1-6 "alkyl" refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, preferably "C". 1-4 "Alkyl". The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or isomers thereof.

[0031] Term "C" 3-6 "Cycloalkyl" should be understood as representing a saturated monovalent monocyclic or bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring having 3, 4, 5, or 6 carbon atoms. The C... 3-6 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0032] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.

[0033] The term "halogen" includes F, Cl, Br, and I.

[0034] The term "solid tumor" refers to an abnormal mass of tissue that typically does not contain cysts or fluid-filled areas. Solid tumors can be benign (not cancerous) or malignant (cancer). In some embodiments, the tumor is metastatic. For the purposes of this disclosure, the term "solid tumor" refers to a malignant solid tumor. The term includes different types of solid tumors named after the cell types that form them, namely sarcomas, carcinomas, and lymphomas.

[0035] The term "pharmaceuticalally acceptable excipient" refers to an excipient that does not cause significant irritation to the organism and does not impair the biological activity and properties of the active compound.

[0036] The term "at least one" refers to one, two, three, four, five or more.

[0037] The term "two or more" refers to two, three, four, five or more kinds.

[0038] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0039] The term “therapeutic effective dose” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in a tissue, system, animal, individual, or human to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in an individual who is susceptible to disease, disorder, or symptom but has not yet experienced or developed the pathology or symptoms of the disease. (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in an individual experiencing or developing the pathology or symptoms of the disease (i.e., prevention of further development of the pathology and / or symptoms). (3) relief of disease: e.g., relief of disease, disorder, or symptom in an individual experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptom). The specific dosage will vary depending on factors such as the specific compound chosen, the dosing regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used. Beneficial effects

[0040] The present invention unexpectedly discovered that the compound of formula I and its pharmaceutically acceptable salt have therapeutic effects on a variety of tumors (gastric cancer, lung cancer, endometrial cancer, pancreatic cancer, liver cancer, oral cancer, breast cancer, and ovarian cancer) carrying the p53-Y220C mutant. Attached Figure Description

[0041] Figure 1: Efficacy experiment in the CB17 / SCID mouse BXPC-3 human pancreatic cancer subcutaneous xenograft model;

[0042] Figure 2: Efficacy experiment in the BALB / c Nude mouse Huh7 human liver cancer subcutaneous xenograft model. Detailed Implementation

[0043] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0044] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0045] Compound I and Compound I-1 can be prepared by the method described in PCT / CN2024 / 101613 (filed on June 26, 2024), and all contents involved in that patent application are incorporated herein by reference.

[0046] The structure of the control compound in this invention is as follows:

[0047] The structure of compound I-1 is as follows:

[0048] Example 1

[0049] Proliferation experiments of cells carrying the p53-Y220C cell line

[0050] 1. Experimental Procedure

[0051] 1) Eight cell lines carrying p53-Y220C (HuH-7, MFE-296, HCC366, HCC1419, and COV362 were purchased from Cobioer; HCC2935 and NCI-H2342 were purchased from ATCC; and KON was purchased from JCRB) were cultured in their respective cell culture media at 37°C in an incubator with a carbon dioxide concentration of 5%.

[0052] 2) When the cell confluence is 75-85%, digest the cells and transfer the cell suspension to a sterile centrifuge tube. Centrifuge at 1000 rpm for 5 min to collect the cells and discard the supernatant. Resuspend the cells in the corresponding culture medium and count them. Seed the cells evenly in a 384-well plate at an appropriate density, 40 μL per well, and culture the cells overnight.

[0053] The specific culture medium and plating conditions are shown in Table 1.

[0054] Table 1 Cell culture medium and plating conditions

[0055] 3) The compound of formula I-1 and the control compound were serially diluted with DMSO and then added to the cell culture plate with I.DOT to make the final DMSO concentration 0.1%.

[0056] 4) Place the cell culture plate in an incubator at 37°C and 5% CO2 for 7 days;

[0057] 5) Remove the cell culture plate from the incubator, equilibrate to room temperature, add 20 μL of CellCounting-Lite 2.0 Luminescent Cell Viability Assay reagent, shake at 350 rpm for 2 min at room temperature, and incubate in the dark for 28 min at room temperature.

[0058] 6) Use BMG to read Luminescence values;

[0059] 7) Analyze the data and compile a report.

[0060] 2. Data Analysis

[0061] Calculation formula:

[0062] Set the negative control reading to 0% inhibition rate and the positive control reading to 100% inhibition rate, and calculate the inhibition rate for each test solution. % Inhibition rate = (Data_Negative Control - Data_Sample) / (Data_Negative Control - Data_Positive Control) * 100%;

[0063] Data_Positive Control: Average readings from the positive control wells; Data_Negative Control: Average readings from the negative control wells;

[0064] IC was calculated by fitting the % inhibition rate and the logarithm of the compound concentration using Graphpad. 50 .

[0065] 3. Experimental Results

[0066] IC50 of compound I-1 and control compound on the proliferation inhibition of 8 p53-Y220C cell lines 50 The values ​​are shown in Table 2.

[0067] Table 2

[0068] Experimental conclusion: Compound I-1 can significantly inhibit the proliferation activity of 8 tumor cell lines containing the p53-Y220C mutant, and the activity is about twice that of the control compound.

[0069] Example 2

[0070] Pharmacodynamic experiments in CB17 / SCID mouse BXPC-3 human pancreatic cancer subcutaneous xenograft model

[0071] 1. Laboratory animals

[0072] Species: Mouse

[0073] Strain: CB17 / SCID

[0074] Age and weight: 6-8 weeks old, weight 16-21 grams

[0075] Sex: Female

[0076] Quantity: 60 (excluding any remaining mice from the grouping)

[0077] Supplier: Shanghai Vital River Laboratory Animal Technology Co., Ltd.

[0078] Husbandry Environment: Animals were kept in the experimental environment for 3-7 days after arrival before the experiment began. Animals were housed in SPF-grade animal rooms using IVC (Independent Ventilation Control) cages (6 animals per cage). Each cage's animal information card indicated the number of animals in the cage, sex, strain, receipt date, drug administration regimen, experiment number, group, and experiment start date. All cages, bedding, and water were sterilized before use. Cages, feed, and water were changed twice a week. The husbandry environment and lighting conditions are as follows:

[0079] Temperature: 20~26℃;

[0080] Humidity: 40-70%;

[0081] Lighting cycle: 12 hours of light, 12 hours of no light (lights on at 8 am to lights off at 8 pm).

[0082] Cage: Made of polycarbonate, with dimensions of 300mm × 180mm × 150mm. Bedding is corn cob, which is changed twice a week.

[0083] Food: Laboratory animals were allowed free access to food throughout the experimental period (sterilized by irradiation, dry granular food).

[0084] Drinking water: Laboratory animals may drink sterilized water freely.

[0085] Cage labeling: Each cage animal information card should indicate the number of animals in the cage, sex, strain, date of receipt, administration regimen, experiment number, group, and experiment start date.

[0086] Animal identification: Laboratory animals are identified by ear tags.

[0087] 2. Cell lines

[0088] Human pancreatic cancer BXPC-3 cells, purchased from ATCC.

[0089] 3. Test drug

[0090] The preparation of the test drug is shown in Table 3.

[0091] Table 3

[0092] 4. Establishment of animal models

[0093] Human pancreatic cancer BXPC-3 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. Cells were routinely digested with trypsin-EDTA two to three times per week and passaged at a ratio of 1:2 to 1:3. When cell saturation reached 80%-90%, the desired number was achieved, cells were harvested, counted, and seeded. 0.2 mL (5 × 10⁶ cells / mL) of the medium was used for seeding. 6 (Number) human pancreatic cancer BXPC-3 cells resuspended in DPBS (containing 0.1 ml of matrix gel, BD, Catalogue: 356234) were subcutaneously inoculated into the right posterior dorsal region of each mouse. Seven days after tumor cell inoculation, the average tumor volume reached 176.17 mmHg. 3 They were administered the medication in groups on the same day.

[0094] The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The tumor-suppressive efficacy of the compound was evaluated using TGI (%), which reflects the tumor growth inhibition rate. The calculation of TGI (%) is as follows: TGI (%) = [(1 - (mean tumor volume at the end of treatment in a certain treatment group - mean tumor volume at the beginning of treatment in that treatment group)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0095] The drug administration information for each group is shown in Table 4. At the end of the experiment, plasma samples were collected from groups G2-G6: plasma was collected from the first 3 mice in each group at 0h, 1h, 2h, and 4h after the last administration; plasma was collected from the last 3 mice in each group at 0.5h, 6h, 9h, and 24h after the last administration.

[0096] Table 4. Administration routes, dosages, and regimens in the BXPC-3 human pancreatic cancer subcutaneous xenograft model.

[0097] The efficacy results of the test compounds in the CB17 / SCID mouse BXPC-3 human pancreatic cancer subcutaneous xenograft model are shown in Figure 1.

[0098] Experimental Results: The results showed that compound I-1 had a significant dose-dependent antitumor effect in the CB17 / SCID mouse BXPC-3 human pancreatic cancer subcutaneous xenograft model. Furthermore, compound I-1 could achieve a lower exposure level (AUC). 0-t The compound 102502 vs 337867 achieved an antitumor effect comparable to the control compound. Detailed efficacy and accompanying pharmacokinetic information are shown in Table 5.

[0099] Table 5. Pharmacodynamics and accompanying pharmacokinetic results of the tested compounds.

[0100] Example 3

[0101] Efficacy experiment in a BALB / c Nude mouse HuH7 subcutaneous xenograft model of human liver cancer

[0102] 1. Laboratory animals

[0103] Species: Mouse

[0104] Strain: BALB / c nude

[0105] Age and weight: 6-8 weeks old, weight 16-20 grams

[0106] Sex: Female

[0107] Quantity: 66 (excluding mice remaining from the group)

[0108] Supplier: Shanghai Vital River Laboratory Animal Technology Co., Ltd.

[0109] 2. Cell lines

[0110] Human hepatocellular carcinoma HuH-7 cells were purchased from the cell bank of the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.

[0111] 3. Test drug

[0112] The preparation of the test drug is shown in Table 6.

[0113] Table 6

[0114] 4. Establishment of animal models

[0115] Human hepatocellular carcinoma HuH-7 cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% CO2. The cells were routinely digested with trypsin-EDTA two to three times per week and passaged at a ratio of 1:2 to 1:3. When the cell saturation reached 80%-90%, the desired number was achieved, and the cells were harvested, counted, and seeded. 0.2 mL (5 × 10⁶ cells / mL) of the solution was used for seeding. 6(Number) human hepatocellular carcinoma HuH-7 cells resuspended in DPBS (containing 0.1 ml of matrix gel, BD, Catalogue: 356234) were subcutaneously inoculated into the right posterior dorsal region of each mouse. Eight days after tumor cell inoculation, the average tumor volume reached 160.13 mmHg. 3 They were administered the medication in groups on the same day.

[0116] The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The tumor-suppressive efficacy of the compound was evaluated using TGI (%), which reflects the tumor growth inhibition rate. The calculation of TGI (%) is as follows: TGI (%) = [(1 - (mean tumor volume at the end of treatment in a certain treatment group - mean tumor volume at the beginning of treatment in that treatment group)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0117] The drug administration information for each group is shown in Table 7. At the end of the experiment, plasma samples were collected from groups G2-G6: plasma was collected from the first 3 mice in each group at 0h, 1h, 2h, and 4h after the last administration; plasma was collected from the last 3 mice in each group at 0.5h, 6h, 9h, and 24h after the last administration.

[0118] Table 7. Administration routes, dosages, and regimens in the HuH-7 human hepatocellular carcinoma subcutaneous xenograft model.

[0119] The efficacy results of the test compounds in the HuH-7 human hepatocellular carcinoma subcutaneous xenograft model are shown in Figure 2.

[0120] Experimental Results: The results showed that compound I-1 had a significant dose-dependent antitumor effect in the HuH-7 human hepatocellular carcinoma subcutaneous xenograft model. Furthermore, compound I-1 could achieve a lower exposure level (AUC). 0-t The drug (TGI: 106474 vs 451314) achieved a superior antitumor effect compared to the control compound (TGI: 76% vs 58%). Detailed efficacy and accompanying pharmacokinetic information are shown in Table 8.

[0121] Table 8. Pharmacodynamics and accompanying pharmacokinetic results of the tested compounds

[0122] Based on detailed pharmacological experiments, this invention demonstrates that the compound of Formula I can inhibit the proliferation of tumor cells in multiple tumor types (such as gastric cancer, non-small cell lung cancer, endometrial cancer, liver cancer, etc.), and shows significant anti-tumor efficacy in CDX models of pancreatic cancer and liver cancer, indicating that it has therapeutic effects on multiple tumor types.

[0123] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The use of at least one of a compound of formula I and a pharmaceutically acceptable salt thereof in the preparation of a medicament; Ra and Re may be the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl.

2. The application according to claim 1, wherein, Ra and Re are independently selected from H, F, Cl, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, isopropoxy, or propoxy, respectively. Preferably, the compound of formula I has the following structure: And / or, the pharmaceutically acceptable salt is an organic salt and / or an inorganic salt of a compound of formula I, for example, the organic salt is selected from at least one of methanesulfonate, lactate, maleate, malate, tartrate, ethylsulfonate, malonate and oxalate, and the inorganic salt is selected from at least one of hydrochloride, phosphate and sulfate.

3. The application according to claim 1 or 2, wherein, The compound of Formula I and / or its pharmaceutically acceptable salts are its amorphous or polymorphic forms.

4. The application according to any one of claims 1-3, wherein, The drug is used to treat one or more of the following diseases or conditions: (1) Tumors carrying the p53-Y220C mutant; (2) Stomach cancer, lung cancer (such as non-small cell lung cancer), endometrial cancer, pancreatic cancer, liver cancer, oral cancer, breast cancer and / or ovarian cancer.

5. The application according to claim 4, wherein, The tumor carrying the p53-Y220C mutant is a solid tumor carrying the TP53Y220C mutant; Preferably, the solid tumor carrying the TP53 Y220C mutant is a locally advanced or metastatic solid tumor carrying the TP53 Y220C mutant; Preferably, the solid tumors carrying the TP53-Y220C mutant include, but are not limited to, gastric cancer, lung cancer (such as non-small cell lung cancer), endometrial cancer, pancreatic cancer, liver cancer, oral cancer, breast cancer and / or ovarian cancer.

6. The application according to claim 1, wherein, The drug also contains pharmaceutically acceptable excipients.

7. The application according to claim 1, wherein, The routes of administration of the drug include, but are not limited to, intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, and in situ administration to the tumor. And / or, the drug is a pharmaceutical preparation: tablet, capsule, pill, granule, solution, suspension, syrup, injection, suppository, inhaler or spray.

8. The application according to claim 1, wherein, The drug is a single-dose formulation.

9. The application according to claim 1, wherein, The drug is a multi-dose formulation comprising more than one unit package, wherein each unit package contains the same amount of the compound of formula I and pharmaceutically acceptable salts of the compound of formula I, or at least two unit packages contain different amounts of the compound of formula I and pharmaceutically acceptable salts of the compound of formula I.

10. The application according to claim 1, wherein, The drug also contains one or more therapeutic agents.

11. A treatment method for tumors carrying the p53-Y220C mutant, comprising administering a therapeutically effective amount of the drug to a patient; Preferably, the tumor carrying the p53-Y220C mutant is a solid tumor carrying the TP53 Y220C mutant; Preferably, the solid tumor carrying the TP53 Y220C mutant is a locally advanced or metastatic solid tumor carrying the TP53 Y220C mutant; Preferably, the solid tumors carrying the TP53-Y220C mutant include, but are not limited to, gastric cancer, lung cancer (such as non-small cell lung cancer), endometrial cancer, pancreatic cancer, liver cancer, oral cancer, breast cancer and / or ovarian cancer.

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