Use of KIF18a inhibitor in treatment of colorectal cancer

Abstract

A use of a KIF18A inhibitor in preparation of a drug for treating colorectal cancer. Pharmacological experiments prove that compound 1 can inhibit the growth of HT-29 colorectal cancer xenografts, and the results show that compound 1 has a significant therapeutic effect on colorectal cancer.

Description

Uses of KIF18A inhibitors in the treatment of colorectal cancer

[0001] This application requires the applicant to have:

[0002] The priority right of the prior application filed with the China National Intellectual Property Administration on June 28, 2024, with patent application number 202410864866.0 and entitled "Use of KIF18A inhibitor in the treatment of colorectal cancer", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the pharmaceutical field, specifically relating to the use of a KIF18A inhibitor in the preparation of a drug for treating colorectal cancer. Background Technology

[0004] Cancer is one of the most serious diseases affecting human health, with mortality and morbidity rates often ranking among the highest of all diseases. Although the quality of life for some patients has been greatly improved with the continuous development and progress of medical technology and drug research, there are still many unmet clinical needs in the search for effective treatments or cures for different cancers, and new targets will provide new possibilities for future cancer drug development.

[0005] Cancer cells exhibit unregulated cell proliferation due to damage or loss of one or more genes that regulate the cell cycle. Various kinases and kinesins have been identified as playing key roles in the regulation and progression of cell cycle and mitosis in both normally dividing cells and cancer cells.

[0006] Kinesin molecules are kinetic proteins that use intracellular microtubules as their orbital pathways; also known as molecular motors, they convert ATP energy into mechanical energy and are closely related to eukaryotic cell division, mitosis, meiosis, tissue and organ growth and development, neuronal development, and signal transduction. Kinesin members share a relatively conserved motor domain. Based on the location of the motor domain in the molecule, the kinesin family is broadly divided into three categories: N-type kinesins, where the amino (-NH2) terminal region of the polypeptide chain contains a motor domain; M-type kinesins, where the middle region contains a motor domain; and C-type kinesins, where the carboxyl (-COOH) terminal region contains a motor domain.

[0007] KIF18A is a member of the N-type Kinesin-8 kinesin family. KIF18A protein is highly expressed in various tumors. Therefore, the development of KIF18A protein inhibitors may be a new breakthrough in cancer treatment. Summary of the Invention

[0008] In order to improve the deficiencies of the prior art, the purpose of the present application is to provide a drug with clear therapeutic effect on colorectal cancer disease.

[0009] The purpose of the present application is achieved by the following technical solutions:

[0010] The present application provides the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating colorectal cancer, wherein the structure of compound 1 is as follows:

[0011] According to an embodiment of the present application, the pharmaceutically acceptable salt is selected from one or more of a sodium salt, a potassium salt, a hydrochloride salt, a p-toluenesulfonate salt, a maleate salt and a methanesulfonate salt of compound 1, and is preferably a p-toluenesulfonate salt.

[0012] According to an embodiment of the present application, the drug comprises a pharmaceutically acceptable carrier or excipient, and is suitable for preparation into an appropriate formulation form such as intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, in situ administration to a tumor, etc.

[0013] According to an embodiment of the present application, the drug is prepared into an oral formulation such as a tablet, a capsule, a pill, a granule, a solution, a suspension, a syrup, an injection (including an injection solution, a sterile powder for injection or a concentrated solution for injection), a suppository, an inhalant or a spray.

[0014] According to an embodiment of the present application, the drug is administered orally.

[0015] According to an embodiment of the present application, the drug is administered once a day.

[0016] The present application also provides a method for preventing and / or treating colorectal cancer disease in a subject, which comprises administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, or a composition containing compound 1 or a pharmaceutically acceptable salt thereof.

[0017] According to an embodiment of the present application, the pharmaceutically acceptable salt is selected from one or more of a sodium salt, a potassium salt, a hydrochloride salt, a p-toluenesulfonate salt, a maleate salt and a methanesulfonate salt of compound 1, and is preferably a p-toluenesulfonate salt.

[0018] According to an embodiment of the present application, the colorectal cancer is adenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma.

[0019] According to an embodiment of the present application, the colorectal cancer is TP53-mutated colorectal cancer.

[0020] According to an embodiment of the present application, the colorectal cancer is recurrent or metastatic advanced colorectal cancer.

[0021] According to an embodiment of the present application, the colorectal cancer is TP53-mutated recurrent or metastatic, advanced colorectal cancer.

[0022] According to an embodiment of the present application, the compound 1 or a pharmaceutically acceptable salt thereof or the composition is administered alone or in combination with other anti-tumor drugs.

[0023] According to an embodiment of the present application, the compound 1 or a pharmaceutically acceptable salt thereof or the composition is administered once a day.

[0024] According to an embodiment of the present application, the compound 1 or a pharmaceutically acceptable salt thereof or the composition is administered orally.

[0025] According to an embodiment of the present application, the combination administration can be simultaneous or sequential administration.

[0026] According to an embodiment of the present application, the daily administration dose of the compound 1 or a pharmaceutically acceptable salt thereof is 0.1-1000 mg, which can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg.

[0027] According to an embodiment of the present application, the subject is a mammal, preferably a human.

[0028] The present application also provides a medicament for preventing or treating colorectal cancer disease in a subject, the medicament being Compound 1 or a pharmaceutically acceptable salt thereof, or a composition containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0029] Advantages of the present application:

[0030] The pharmacological experiment of the present application proves that Compound 1 can inhibit the growth of HT-29 colorectal cancer heterograft tumor. It is shown that Compound 1 has obvious therapeutic effect on colorectal cancer. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1: Line graph of the influence of tumor volume in mice of HT-29 xenograft tumor model.

[0032] Figure 2: Schematic diagram of tumor weight in mice of HT-29 xenograft tumor model.

[0033] Figure 3: Line graph of the influence of body weight in mice of HT-29 xenograft tumor model.

[0034] TERMS EXPLANATION AND DEFINITION

[0035] The term "subject" herein refers to an animal, such as a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans.

[0036] The term "therapeutically effective amount" or "effective amount" herein refers to the amount of a compound disclosed and / or described herein that, when administered to a patient in need of such treatment, is sufficient to effect treatment as defined herein. The therapeutically effective amount of a compound can be an amount sufficient to treat a disease responsive to modulation (e.g., inhibition) of KIF18A or to treat colorectal cancer. The therapeutically effective amount will vary depending, for example, on the subject and disease condition being treated, the subject's body weight and age, the severity of the disease condition, the particular compound, the dosing regimen to be followed, the timing and mode of administration, factors which can be readily determined by one of ordinary skill in the art.

[0037] The term "treatment" herein includes one or more of: inhibiting the disease or condition; slowing or arresting the development of clinical symptoms of the disease or condition; and / or relieving the disease or condition (i.e., causing regression or remission of clinical symptoms), and complete or partial reduction of clinical symptoms of the disease or condition.

[0038] The term "therapeutic effect" herein refers to the effect caused by the treatment, which is manifested at the cellular level as the inhibition rate of cell growth or the mortality rate of cells, at the animal level as the change, usually the alleviation or improvement of the symptoms of the disease or disease condition, or the cure of the disease or disease condition.

[0039] The term "pharmaceutically acceptable salt" herein means that the compound can exist in the form of various pharmaceutically acceptable salts. If the compound has a basic center, it can form an acid addition salt; if the compound has an acidic center, it can form a base addition salt; if the compound contains both an acidic center and a basic center, it can also form an internal salt. DETAILED DESCRIPTION

[0040] The present application will be further described in conjunction with specific examples. It should be understood that the following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is included in the scope intended to be protected by the present application.

[0041] The specific preparation method of Compound 1 is referred to the content described in the patent document of WO2024051755A1.

[0042] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0043] Example 1: Pharmacodynamic effect test of Compound 1 on human colorectal cancer HT-29 cell xenograft tumor mice

[0044] 1.1 Purpose of the experiment

[0045] To observe the therapeutic effect of Compound 1 on human colorectal cancer HT-29 cell xenograft tumor mice, evaluate its effect, and preliminarily explore its mechanism of action, and compare it with AMG650, to provide experimental basis for clinical trials.

[0046] 1.2 Experimental materials

[0047] 1.2.1 Experimental reagents

[0048] 1.2.2 Experimental instruments

[0049] 1.3 Test drugs

[0050] AMG650, batch number: EB2302070-048P1; storage condition: 2-8℃; production and sample sending unit: Changchun Jin Sai Pharmaceutical Co., Ltd.

[0051] Compound 1, batch number: EB2302070-072P1; storage condition: 2-8℃; production and sample sending unit: Changchun Jin Sai Pharmaceutical Co., Ltd.

[0052] Solvent components: 20% PEG400 + 10% VE-TPGS + 70% aqueous solution containing 10% hydroxypropyl-β-cyclodextrin (HP-β-CD).

[0053] The preparation method is as follows: an appropriate amount of test sample is accurately weighed into a suitable container, and the above-mentioned solvent components are added step by step and ultrasonically vortexed, and a clear solution is obtained after each step before adding the next component. The final solution after preparation is a clear and transparent solution, which is used for administration.

[0054] The storage conditions of the administration solution are as follows: the preparation frequency is once a week, and each preparation is divided and stored at -20°C. Before administration, it is placed at room temperature.

[0055] 1.4 Cell lines

[0056] The human colorectal cancer cell line HT-29 was purchased from the Cell Bank of the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.

[0057] 1.5 Experimental animals

[0058] Species and strain: Balb / c Nude mice.

[0059] Gender and age: female, 6-8 weeks old.

[0060] Source of animals: Shanghai Vantoll Life Experimental Animal Co., Ltd. The animal qualification certificate is: 20231030Abzz0619000218.

[0061] Raising conditions: raised in polypropylene mouse boxes, with a maximum of 5 animals per box. Temperature: set temperature range 20-26°C, humidity: set humidity range 40%-70%, light: 12 hours light and 12 hours dark alternately.

[0062] Establishment of animal models: HT-29 cells were cultured in vitro in monolayer, and the culture medium was RPMI-1640 medium, cultured at 37°C with 5% CO2. Routine digestion treatment was performed with trypsin-EDTA (0.25% trypsin-EDTA) every one to three times a week, and the passage ratio was 1:2-1:3. When the cell saturation was 80%-90% and the number reached the requirement, the cells were collected, counted, and inoculated. 0.2 mL / 5 x 10 6 HT29 cells were subcutaneously inoculated in the right back of each mouse. Six days after tumor cell inoculation, the average tumor volume reached 125 mm 3 , and the mice were grouped and administered on the same day.

[0063] The experimental grouping is as follows:

[0064] According to the relevant regulations of animal welfare, if an individual experimental animal meets any of the following conditions during the experiment, the animal will be removed from the experimental group and euthanized. (1) The animal's body weight decreases by more than 20% compared to Day 0 (BWL≥20%) and is scheduled for euthanasia; (2) The animal has severe adverse reactions such as blindness, paralysis, etc.; (3) The tumor volume is greater than 2000mm 3 ; (4) Open ulcers form on the surface of the tumor. After the last weighing at the end of the experiment, the remaining animals are euthanized and killed with CO2, samples are collected, and the tumor is weighed and photographed

[0065] 1.6 Experimental observation indicators and detection methods

[0066] During the experiment, the animal's body weight and tumor volume were measured twice a week, and the animal's clinical symptoms were observed and recorded daily.

[0067] The formula for calculating the tumor volume (TV) is: 1 / 2×a×b 2 , where a and b are the length and width of the tumor measurement, respectively.

[0068] The formula for calculating the tumor inhibition rate (%TGI TV ) is: 1-(TV Tn -TV T0 ) / (TV Cn -TV C0 )*100%, TV C is the average tumor volume of the negative control group, TV T is the average tumor volume of the treatment group, TV T0 is the average tumor volume of the treatment group before treatment, and TV C0 is the average tumor volume of the negative control group before treatment.

[0069] The formula for calculating the animal body weight change (%BWC) is: (BW t -BW0) / BW0×100%, where BW t is the animal's body weight at each measurement, and BW0 is the animal's body weight at the time of grouping.

[0070] According to the Chinese NMPA "Technical Guidelines for Nonclinical Studies of Cytotoxic Antitumor Drugs" (November 2006), %T / C≤40% and P<0.05 by statistical analysis are considered effective. If the number of drug-related animal deaths exceeds 20%, the drug dose is considered to have severe toxicity.

[0071] 1.7 Statistical analysis

[0072] The comparison between groups was analyzed by one-way ANOVA. No significant difference was considered when p>0.05, significant difference was considered when p<0.05, obvious significant difference was considered when p<0.01, and extremely significant difference was considered when p<0.001.

[0073] 1.8 Experimental results

[0074] As shown in Figure 1, the TGI of AMG650 at 30 mg / kg and 100 mg / kg was 76.96% and 108.75%, respectively, and the TGI of Compound 1 at 10 mg / kg, 30 mg / kg and 100 mg / kg was 60.34%, 75.12% and 96.75%, respectively.

[0075] As shown in Figure 2, the tumor weight of the model group mice was 963±120 mg, the tumor weight of AMG650 at 30 mg / kg and 100 mg / kg was 322±94 mg and 63±26 mg, respectively, and the tumor weight of Compound 1 at 10 mg / kg, 30 mg / kg and 100 mg / kg was 453±117 mg, 318±99 mg and 168±22 mg, respectively.

[0076] As shown in Figure 3, AMG650 and Compound 1 at all doses had no significant effect on the body weight change of the animals relative to the solvent group, and no obvious toxicity was observed.

[0077] In summary, in the HT-29 colorectal cancer heterogenous tumor mouse model, Compound 1 (10 mg / kg, 30 mg / kg and 100 mg / kg) and AMG650 significantly inhibited tumor growth, showing obvious therapeutic effect on colorectal cancer.

[0078] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. Use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of colorectal cancer, wherein, The structure of the compound 1 is shown below: Preferably, the pharmaceutically acceptable salt is selected from one or more of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate and mesylate of the compound, preferably p-toluenesulfonate.

2. Use according to claim 1, wherein, The colorectal cancer is adenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma; or the colorectal cancer is TP53-mutated colorectal cancer; or the colorectal cancer is recurrent or metastatic advanced colorectal cancer; preferably, the colorectal cancer is TP53-mutated recurrent or metastatic advanced colorectal cancer.

3. Use according to claim 1 or 2, wherein, The medicament comprises a pharmaceutically acceptable carrier or excipient, and is suitable for preparation into an intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, in situ administration to tumor, etc. Preferably, the medicament is administered orally; preferably, the medicament is administered once a day.

4. Use according to claim 1 or 2, wherein, The medicament is prepared into an oral preparation, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays.

5. A method of preventing and / or treating colorectal cancer disease in a subject, wherein, The methods include administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a composition containing Compound 1, or a pharmaceutically acceptable salt thereof, Preferably, the pharmaceutically acceptable salt is selected from one or more of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate and mesylate of the compound, preferably p-toluenesulfonate.

6. The method of claim 5, wherein, The colorectal cancer is adenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma; or the colorectal cancer is TP53-mutated colorectal cancer; or the colorectal cancer is recurrent or metastatic advanced colorectal cancer; preferably, the colorectal cancer is TP53-mutated recurrent or metastatic advanced colorectal cancer.

7. The method of claim 5 or 6, wherein, The compound 1 or its pharmaceutically acceptable salt or the composition thereof is administered alone or in combination with other anti-tumor drugs; preferably, the administration alone or in combination is once a day; preferably, the administration mode is oral.

8. The method of claim 7, wherein, The combination administration can be simultaneous or sequential administration.

9. The method of claim 5 or 6, wherein, The daily administration dose of the compound 1 is 0.1-1000 mg, which can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg.

10. The method according to claim 5, wherein, The subject is a mammal, preferably a human.

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