Application of compound rociletinib in preparation of medicine for treating acute liver injury by inhibiting ferroptosis

Abstract

The invention discloses an effect of a compound rociletinib in acute liver injury by inhibiting ferroptosis, and belongs to the technical field of programmed cell death (ferroptosis) inhibitors. When acute liver injury is treated, the intracavitary injection dosage is 20 mg / kg, and intraperitoneal injection is performed twice at an interval of 1 h during treatment. The application of the rociletinib in treating the acute liver injury has the beneficial effects that the application of the rociletinib in treating the acute liver injury is provided, and particularly, the ferroptosis inhibitor rociletinib can be applied to treating / relieving the acute liver injury. According to the application disclosed by the invention, a ferroptosis inhibitor rociletinib acts on a mouse acute liver injury model caused by ConA to improve liver histology, liver inflammation tissues, ALT / AST levels and the like, so that a treatment effect is achieved. The application has the main advantages that evidence of rociletinib in the ferroptosis inhibition process is provided, a new theoretical basis is provided for treatment of acute liver injury, and the application has profound application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of programmed cell death (ferroptosis) inhibitors, and specifically relates to the use of rociletinib as a ferroptosis inhibitor, and the use of the above-mentioned drug in the field of acute liver injury treatment. Background Art

[0002] Existing programmed cell death includes: pyroptosis, apoptosis, necroptosis, autophagy, etc., and ferroptosis is a new type of programmed cell death, which is an iron and reactive oxygen species (ROS)-dependent regulated cell death. Different from the morphological characteristics of other cell deaths, the mitochondria of ferroptotic cells are smaller than normal mitochondria, and the mitochondrial membrane density is concentrated, the mitochondrial cristae are reduced or disappeared, and the mitochondrial outer membrane is ruptured.

[0003] A large number of studies have shown that ferroptosis is involved in the occurrence and development of many diseases, and the mechanism is relatively complex; liver disease is currently a common public safety issue in the world, threatening the health of many people. What is more serious is that the incidence of many liver diseases is gradually increasing. The liver is an important metabolic organ in the human body and has many important physiological functions. It is not only the center of material metabolism, but also an important secretion, excretion, biotransformation and barrier organ. The liver is the main site of iron storage. When there is an excess of iron, the liver will become the main target organ for damage and can lead to liver fibrosis and liver cancer. Iron metabolism is related to ferroptosis, and regulating ferroptosis can affect the course of liver disease.

[0004] ConA is often used to make acute liver injury models. TNF-α can directly damage liver cells and lead to liver cell apoptosis. The pathological characteristics of the ConA-induced mouse liver injury experimental animal model are mainly immune liver injury caused by activated T lymphocytes. After ConA was intravenously injected into mice, most of it accumulated in the liver, indicating that the liver is the target organ of ConA-induced toxicity in vivo.

[0005] Acute liver injury refers to abnormal liver function caused by various reasons. Liver injury is the prerequisite for acute liver injury. Severe liver injury can lead to liver failure in patients, thus threatening their lives. There are many reasons for liver injury, the main reasons are viral infection, improper medication, excessive ethanol intake, etc. Therefore, it is urgent to develop new therapeutic drugs targeting its pathogenesis.

[0006] The compound rociletinib is an orally available EGFR inhibitor that can inhibit the activity of EGFRL858R / T790M and EGFRWT, with IC50 values ​​of 21.5nM and 303.3nM, respectively. Rociletinib is an irreversible, mutation-selective EGFR inhibitor, mainly used to treat patients with non-small cell lung cancer (NSCLC) with initial activating EGFR mutations and dominant resistance mutation T790M. However, there have been no reports of using rociletinib as a cell ferroptosis inhibitor and for the treatment of acute liver injury. Summary of the invention

[0007] The technical problem to be solved by the present invention is how to propose a new medical use of the compound rociletinib.

[0008] The present invention solves the above technical problems through the following technical means:

[0009] The first aspect of the present invention provides the use of the compound rociletinib as a cell ferroptosis inhibitor.

[0010] The structural formula of the compound rociletinib is shown below, CAS: 1374640-70-6.

[0011]

[0012] The second aspect of the present invention provides the use of the compound rociletinib in any of the following:

[0013] (1) Use in the preparation of drugs for preventing or treating diseases related to ferroptosis;

[0014] (2) Application in the preparation of drugs for inhibiting lipid peroxidation levels during ferroptosis;

[0015] (3) Use in the preparation of drugs for reducing serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST);

[0016] (4) Application in the preparation of drugs for reducing liver GSH levels;

[0017] (4) Application in the preparation of drugs for inhibiting the expression of ferroptosis-related proteins ACSL4 and NRF2;

[0018] (5) Application in the preparation of drugs for reducing the levels of inflammatory factors IL-1β and TNF-α in serum.

[0019] Preferably, the diseases associated with ferroptosis include but are not limited to cerebral hemorrhage, acute liver injury, acute kidney injury, liver and kidney ischemia-reperfusion injury, diabetes, Parkinson's disease and other related diseases.

[0020] Preferably, when treating acute liver injury, the compound rociletinib is injected intraperitoneally at a dose of 20 mg / kg, and is injected intraperitoneally twice with an interval of 1 hour.

[0021] Preferably, in (1)-(5), the drug further comprises a chemically acceptable salt of the compound rociletinib.

[0022] Preferably, in (1)-(5), the drug further comprises a pharmaceutically acceptable carrier and / or excipient.

[0023] Preferably, the pharmaceutically acceptable excipient is selected from one or more of a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, a surfactant, an adsorption carrier and a lubricant.

[0024] Preferably, in (1)-(5), the drug is prepared into a pharmaceutically acceptable dosage form.

[0025] Preferably, the dosage forms include injections, solutions, gels, suspensions, implants, creams, embolics, capsules, tablets, pills and oral solutions.

[0026] The third aspect of the present invention proposes a disease model of acute liver injury induced by concanavalin A (ConA), and uses rociletinib to treat the ConA-induced acute drug-induced liver injury model. Rociletinib can repair liver tissue damage and necrosis caused by ConA, reduce ALT / AST levels, inflammatory factor levels and liver GSH levels in mouse serum, and also has obvious therapeutic effects on acute drug-induced liver injury induced by concanavalin A (ConA).

[0027] The beneficial effects of the present invention are:

[0028] 1. The present invention proposes a new use of the compound rociletinib, which can reduce the increase of lipid peroxidation and reactive oxygen species in the process of ferroptosis, inhibit the process of ferroptosis induced by different ferroptosis inducers, and reduce the cell death rate, thereby achieving the therapeutic effect of diseases related to the ferroptosis mechanism. The ferroptosis inhibitor reduces the levels of ALT and AST and various inflammatory factors in acute liver injury and restores the GSH level in liver tissue, thereby achieving the purpose of treating ferroptosis-related diseases.

[0029] 2. The present invention provides the use of the compound rociletinib in the treatment of acute liver injury, specifically, the described ferroptosis inhibitor rociletinib can be used to treat / alleviate acute liver injury. The present invention acts on the mouse acute liver injury model caused by ConA through the ferroptosis inhibitor rociletinib, improving liver histology, liver inflammatory tissue, ALT / AST levels, etc., thereby playing a therapeutic role. The present invention provides evidence of rociletinib in the process of inhibiting ferroptosis, providing a new theoretical basis for the treatment of acute liver injury, and has far-reaching application value.

[0030] 3. Based on the study of the mechanism of cell death, the present invention discovered through screening and cell activity experimental tests that the compound rociletinib can be used as an inhibitor targeting cell ferroptosis, and provided treatment measures for rociletinib in the treatment of acute liver injury. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 In Example 1 of the present invention, rociletinib has a significant inhibitory effect on the incidence of cell ferroptosis induced by different concentrations of RSL3;

[0032] Figure 2 In Example 1 of the present invention, rociletinib has a significant inhibitory effect on the incidence of cell ferroptosis induced by different ferroptosis inducers RSL3, Erastin and FIN56;

[0033] Figure 3 In Example 1 of the present invention, rociletinib has a significant inhibitory effect on ferroptosis of different cells induced by RSL3, wherein Figure 3 a is the change of cell survival rate in MDA-MB-231 cells induced by RSL3. Figure 3 b is the change of cell survival rate in 4T1 cells induced by RSL3. Figure 3 c is a graph showing the changes in cell survival rate in MCA-205 cells induced by RSL3-induced ferroptosis;

[0034] Figure 4 In Example 1 of the present invention, rociletinib reduces the increase in cellular lipid peroxidation induced by RSL3;

[0035] Figure 5 The treatment of liver injury induced by concanavalin A (ConA) with rociletinib in Example 1 of the present invention (HE stained sections);

[0036] Figure 6The rociletinib treatment in Example 1 of the present invention reduces the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of concanavalin A (ConA)-induced mice, wherein Figure 6 a is the result diagram of AST level detection. Figure 6 b is the result of ALT level detection;

[0037] Figure 7 The rociletinib treatment in Example 1 of the present invention increases the level of glutathione (GSH) in liver tissue of mice induced by concanavalin (ConA);

[0038] Figure 8 The changes of rociletinib in Example 1 of the present invention in treating the ferroptosis-related proteins in the liver tissue of mice induced by concanavalin (ConA);

[0039] Fig. 9 The effect of rociletinib in Example 1 of the present invention on the reduction of inflammatory factors related to liver tissue in mice induced by concanavalin (ConA) is shown in FIG. Fig. 9 a is the result of ELISA test on IL-1β level. Fig. 9 b is the result of ELISA test on TNF-α level. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0041] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0042] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0043] Embodiment 1:

[0044] 1 Materials and Methods

[0045] 1.1 Preparation of experimental raw materials:

[0046] Compounds rociletinib, Erastin and RSL3 were purchased from Shanghai Taoshu Biotechnology Co., Ltd., dissolved in sterile DMSO (dimethyl sulfoxide) and prepared into the required concentrations. CCK-8 (Cell Counting Kit-8 reagents): purchased from Shanghai Taoshu Biotechnology Co., Ltd., with the catalog number C0005; RSL3: purchased from Shanghai Taoshu Biotechnology Co., Ltd., with the catalog number T3646; Erastin: purchased from Shanghai Taoshu Biotechnology Co., Ltd., with the catalog number T1765; FIN56: purchased from MedChemExpress, with the catalog number HY-103087; Tissue / cell glutathione (GSH) detection kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; BCA protein concentration determination kit: purchased from Biotech, with the catalog number P0011; lactate dehydrogenase cytotoxicity detection kit: Biotech, with the catalog number C0016; mouse aspartate aminotransferase (ALT) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; mouse alanine aminotransferase (AST) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; creatinine (CRE) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; urea nitrogen (BUN) kit: purchased from Nanjing Jiancheng Bioengineering Research Institute Co., Ltd.; BODIPY 581 / 591C11: Invitrogen, D3861; Mouse IL-1β ELISA kit: R&D, DY401; Mouse IL-6DuoSet ELISA: R&D, DY406.

[0047] 1.2 Culture of HT-1080 human fibrosarcoma cells:

[0048] Culture conditions of HT-1080 human fibrosarcoma cell line: DMEM high glucose medium (GIBCO) containing 10% FBS (GIBCO), 37°C, 5% CO2, saturated humidity incubator.

[0049] 1.3Rociletinib inhibits RSL3-induced ferroptosis

[0050] HT1080 cells in mature growth phase were used, digested with trypsin for 1 min, resuspended, centrifuged at 1000 rpm for 3 min, and the supernatant was discarded. 6000 cells were inoculated in each well of a 96-well plate. After the cells adhered to the wall, they were divided into the following groups: normal control group (Control): adding the corresponding volume of DMSO; RSL3 treatment group: each well was treated with 1μM RSL3 for 8h; RSL3+ different concentrations of rociletinib group, 5μM, 2.5μM and 1μM rociletinib were added to the culture medium 1h before adding RSL3 with different final concentrations for 8h. After 8h, CCK-8 was used to detect cell viability, and the experiment was repeated 3 times.

[0051] Results Figure 1 From the analysis of cell activity results in the ferroptosis-induced group, 1μM RSL3 successfully induced cell ferroptosis. From the cell activity detection in the rociletinib-administered group, it can be seen that rociletinib pretreatment can inhibit cell ferroptosis. This indicates that rociletinib can inhibit RSL3-induced ferroptosis.

[0052] 1.4Rociletinib inhibits ferroptosis induced by Erastin and FIN56

[0053] HT1080 cells in mature growth phase were used, digested with trypsin for 1 min, resuspended, centrifuged at 1000 rpm for 3 min, and the supernatant was discarded. 6000 cells were inoculated in each well of a 96-well plate, and after the cells adhered to the wall, they were divided into the following groups: normal control group (Control): adding corresponding volume of DMSO; FIN56 and Erastin treatment group: each well was treated with 40μM FIN56 or 20μM Erastin for 8h; FIN56 / Erastin+rociletinib group, 5μM rociletinib was added to the culture medium 1h before adding different final concentrations of FIN56 / Erastin for 8h. After 8h, CCK-8 was used to detect cell viability, and the experiment was repeated 3 times.

[0054] Results Figure 2 , Cell activity results analysis showed that 40μM FIN56 or 20μM erastin successfully induced cell ferroptosis, and rociletinib pretreatment could inhibit cell ferroptosis, indicating that rociletinib can inhibit ferroptosis induced by 40μM FIN56 or 20μM erastin.

[0055] 1.5Rociletinib has an inhibitory effect on RSL3-induced ferroptosis in different cells

[0056] MDA-MB-231, 4T1 and MCA205 cells in mature growth phase were used respectively. After trypsin digestion for 1 min, they were resuspended and centrifuged at 1000 rpm for 3 min. The supernatant was discarded and about 1*10 cells of each type were used. 4 / well were plated in 96-well plates and divided into: normal control group (Control): add corresponding volume of DMSO; RSL3 treatment group: each well was treated with 1μM RSL3 for 8h; RSL3 + different concentrations of rociletinib group, 5μM, 2.5μM and 1μM rociletinib were added to the culture medium 1h before adding RSL3 with different final concentrations for 8h. After 8h, CCK-8 was used to detect cell survival rate, and the experiment was repeated 3 times.

[0057] Results Figure 3 , The results of cell activity analysis of the RSL3-induced group showed that 1 μM RSL3 successfully induced cell ferroptosis. Cell activity detection in the drug-treated group showed that rociletinib pretreatment could inhibit cell ferroptosis, indicating that rociletinib can inhibit RSL3-induced ferroptosis in different cells.

[0058] 1.6Rociletinib inhibits lipid peroxidation during ferroptosis in vitro:

[0059] HT1080 cells in mature growth stage were used, digested with trypsin for 1 min, resuspended, centrifuged at 1000 rpm for 3 min, and the supernatant was discarded. 4 The cells were plated in 6-well plates. The groups were: normal control group; RSL3 treatment group: 1μM RSL3 was added to the culture medium for 6-8h; RSL3+rociletinib treatment group: 5μM rociletinib was added 1h before 1μMRSL3 was added to the culture medium. After the cells in each group were treated, the cell culture supernatant was removed, 500μL serum-free DMEM and 5μM BODIPY 581 / 591C11 were added to each well, and the 6-well plate was placed in a 37℃ incubator for 30min. Trypsin was added to digest the cells. After 1min, the digestion was terminated, and the cells were transferred to EP tubes and centrifuged at 4℃ for 5min, 3000rpm, and the cells were collected and resuspended in ice PBS and centrifuged again to collect the cells. The washing process was repeated 3 times.

[0060] Results Figure 4 When cells were treated with RSL3 alone, lipid peroxidation caused by ferroptosis was significantly increased. The addition of rociletinib could inhibit the level of lipid peroxidation. Therefore, rociletinib can inhibit the increase of lipid peroxidation during ferroptosis.

[0061] 1.7 The alleviating effect of rociletinib on concanavalin A (ConA)-induced acute liver injury in mice

[0062] Animal grouping: Fifteen C57BL / 6 mice aged 8-10 weeks were selected and randomly divided into the following three groups: control group; ConA group (500 mg / kg); rociletinib (40 mg / kg) + ConA group (500 mg / kg).

[0063] Animal treatment: The acute liver injury model in mice was induced by intraperitoneal injection of concanavalin (ConA) (500 mg / kg). A certain amount of ConA was weighed, dissolved in sterile PBS, and administered by tail vein injection. Rociletinib was dissolved in sterile PBS and injected intravenously 1 hour before the injection of ConA. At the time of intraperitoneal injection of ConA, blood samples were collected from the retro-orbital venous plexus for liver function testing. Then, the mice were dissected 24 hours later, and the liver tissue was immediately removed. H&E stained sections were made after fixation with 4% paraformaldehyde, and the results of pathological sections were used to determine whether the induction was successful.

[0064] Results Figure 5 , Pathological section analysis showed that the liver damage in the ConA-treated group increased significantly, and the liver damage was significantly alleviated after rociletinib treatment, suggesting that rociletinib can treat liver damage in vivo.

[0065] Detection of AST and ALT in mouse serum: Collect the whole blood of mice in each group, let it stand for 1 to 2 hours, and directly centrifuge it at low speed to separate the serum for later use. Dilute the separated serum sample 5 times, and operate the samples according to the product instructions of the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) detection kits.

[0066] Results Figure 6 , ALT and AST test results analysis, the rociletinib treatment group serum ALT, AST levels were significantly reduced, indicating that rociletinib has a positive effect in reducing ConA-induced liver damage and restoring liver function.

[0067] Detection of GSH levels in mouse liver tissue: The right lobe of the mouse liver was removed and the tissue was accurately weighed. According to the ratio of weight (g) / volume (mL) = 1 / 9, 9 times PBS was added to make a tissue homogenate. The mixture was centrifuged at 2500 rpm for 5 min, the supernatant was taken, and the operation was performed according to the instructions of the GSH kit.

[0068] Results Figure 7 ,Analysis of GSH test results showed that the GSH level in the rociletinib-treated group was significantly increased, indicating the beneficial effects of rociletinib in alleviating ConA-induced oxidative stress and maintaining stable GSH levels.

[0069] Western blot detection: Use RIPA lysis buffer to lyse the tissue on ice for 20 minutes, extract the protein, perform BCA quantification, separate by polypropylene gel electrophoresis, transfer to PVDF membrane, block at room temperature for 1 hour, add diluted primary antibody (primary antibody is diluted 1:1000), incubate at 4°C overnight, incubate with secondary antibody (1:10000) for 1 hour on the second day, wash the membrane and collect images using ECL chemiluminescence imaging system.

[0070] Results Figure 8 ,Western blot analysis showed that rociletinib treatment inhibited the expression of ferroptosis-related proteins ACSL4 and NRF2.

[0071] ELISA test: After the collected mouse blood samples were allowed to stand at room temperature for 2 hours, they were centrifuged at 4°C, 1500 rpm for 10 minutes, and the supernatant was taken for ELISA test.

[0072] Results Fig. 9 , ELISA test results analysis, rociletinib treatment reduced the levels of inflammatory factors related to ConA-induced liver tissue in mice, including Fig. 9 a is the result of ELISA test on IL-1β level. Fig. 9 b is the result of ELISA test on TNF-α level.

[0073] 1.8 Statistical methods

[0074] The statistical analysis was performed using R software, and the experimental data were expressed as Mean ± SEM. The intergroup comparisons in cell and animal experiments were performed using Tukey's test (ANOVA), and the comparisons between two groups were performed using Student's test. P < 0.05 was considered statistically significant, and different letters indicate P < 0.05.

[0075] 2 Results

[0076] 2.1Rociletinib inhibits RSL3-induced ferroptosis in HT-1080 cells

[0077] The experimental results showed that, compared with the control, the ferroptosis inducer RSL3 stimulation could significantly kill cells; and rociletinib could significantly inhibit RSL3-induced cell death (p<0.01). Figure 1 As shown. This indicates that rociletinib has a significant inhibitory effect on RSL3-induced cell ferroptosis.

[0078] 2.2Rociletinib inhibits ferroptosis induced by different ferroptosis inducers, Erastin and FIN56, in HT-1080 cells

[0079] The experimental results showed that compared with the control, the ferroptosis inducers Erastin and FIN56 stimulation could significantly kill cells; and rociletinib could significantly inhibit the cell death induced by Erastin and FIN56 (p<0.01). Figure 2 shown.

[0080] 2.3Rociletinib has an inhibitory effect on RSL3-induced ferroptosis in different cells;

[0081] The experimental results showed that rociletinib could inhibit ferroptosis induced by RSL3 in both human cells (MDA-MB-231) and mouse cells (4T1, MCA205). Figure 3 shown.

[0082] 2.4Rociletinib reduces the increase in cellular lipid peroxidation induced by RSL3

[0083] The experimental results showed that, compared with the control, ferroptosis inducer RSL3 stimulation could significantly increase cellular lipid peroxidation; while rociletinib could significantly inhibit RSL3-induced cellular lipid peroxidation (p<0.01). Figure 4 As shown. This indicates that rociletinib has a significant inhibitory effect on the increase of cellular lipid peroxidation induced by RSL3.

[0084] 2.5 The alleviating effect of rociletinib on concanavalin A (ConA)-induced acute liver injury in mice

[0085] The experimental results showed that the necrotic area in the rociletinib-treated group was significantly reduced compared with the concanavalin A (ConA)-treated group. Figure 5 As shown in the figure, the levels of ALT and AST in the serum of the rociletinib-treated group were significantly reduced. Figure 6 As shown; rociletinib treatment increased the level of glutathione (GSH) in liver tissue of mice induced by concanavalin A (ConA). Figure 7 As shown; rociletinib treatment inhibits the expression of ferroptosis-related proteins ACSL4 and NRF2, as shown Figure 8 As shown in the figure, rociletinib can reduce the levels of IL-1β and TNF-α in the liver tissue of mice induced by concanavalin A (ConA). Fig. 9 Therefore, rociletinib has a significant alleviating effect on acute drug-induced liver injury induced by concanavalin A (ConA) in mice.

[0086] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The use of the compound rociletinib as a cell ferroptosis inhibitor, wherein the structural formula of the compound rociletinib is 2. Use of the compound rociletinib in any of the following: (1) Use in the preparation of drugs for preventing or treating diseases related to ferroptosis; (2) Application in the preparation of drugs for inhibiting lipid peroxidation levels during ferroptosis; (3) Use in the preparation of drugs for reducing serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST); (4) Application in the preparation of drugs for reducing liver GSH levels; (4) Application in the preparation of drugs for inhibiting the expression of ferroptosis-related proteins ACSL4 and NRF2; (5) Application in the preparation of drugs for reducing the levels of inflammatory factors IL-1β and TNF-α in serum.

3. The use according to claim 2, characterized in that: The diseases associated with ferroptosis include cerebral hemorrhage, acute liver injury, acute kidney injury, liver and kidney ischemia-reperfusion injury, diabetes, and Parkinson's disease.

4. The use according to claim 3, characterized in that: When treating acute liver injury, the compound rociletinib is injected intraperitoneally at a dose of 20 mg / kg, and is injected intraperitoneally twice with an interval of 1 hour.

5. The use according to claim 2, characterized in that: In (1)-(5), the drug also includes a chemically acceptable salt of the compound rociletinib.

6. The use according to claim 2, characterized in that: In (1)-(5), the drug further comprises a pharmaceutically acceptable carrier and / or excipient.

7. The use according to claim 6, characterized in that: The pharmaceutically acceptable excipient is selected from one or more of a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, a surfactant, an adsorption carrier and a lubricant.

8. The use according to claim 2, characterized in that: In (1)-(5), the drug is prepared into a pharmaceutically acceptable dosage form.

9. The use according to claim 8, characterized in that: The dosage forms of the drug include injection, solution, gel, suspension, implant, cream, embolization, capsule, tablet, pill and oral solution.

10. A disease model of acute liver injury induced by concanavalin A, characterized in that: Rociletinib was used to treat the ConA-induced acute drug-induced liver injury model.

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