Composition for enhancing anti-cancer effect of KRAS G12C gene mutation therapeutic agent containing aripiprazole as active ingredient
Aripiprazole compositions enhance the anti-cancer efficacy of KRAS G12C gene mutation therapeutic agents by inducing apoptosis in cancer cells, addressing the limitations of existing therapies by increasing NOXA protein expression and PARP cleavage.
Patent Information
- Application Number
- CN202380039701.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-05-03
- Filing Date
- 2023-05-10
- Publication Date
- 2024-12-20
AI Technical Summary
Current KRAS G12C gene mutation therapeutic agents, such as sotorasib and adagrasib, have limited efficacy in treating cancers with brain metastases, and BH3-only proteins alone are insufficient to induce significant apoptosis due to binding by anti-apoptotic proteins like BCL2 family members.
A pharmaceutical and health functional food composition comprising aripiprazole as an active ingredient, enhancing the anti-cancer effect of KRAS G12C gene mutation therapeutic agents by inducing apoptosis through increased NOXA protein expression and PARP cleavage, either alone or in combination with these agents.
Aripiprazole significantly enhances the anti-cancer effect of KRAS G12C gene mutation therapeutic agents by inducing apoptosis in cancer cells, particularly through increased NOXA protein expression and PARP cleavage, demonstrating superior results when co-administered with these agents.
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Figure CN119173265A_ABST
Abstract
Description
Technical Field
[0001] The present disclosure relates to a composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, the composition comprising aripiprazole as an active ingredient, and more particularly, to a composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, the composition being capable of treating cancer by acting as an anti-cancer effect enhancer of the KRAS G12C gene mutation therapeutic agent in co-treatment with aripiprazole. Background Art
[0002] The KRAS G12C mutation is involved in the development of cancer by activating a mutation from glycine to cysteine, which occurs at codon 12 of the KRAS gene. It is known that approximately 40% of patients with KRAS G12C-mutant non-small cell lung cancer develop brain metastases, and the overall prognosis of patients with brain metastases is poor. Sotorasib, a therapeutic agent for the KRAS G12C gene mutation, is currently in clinical trials for non-small cell lung cancer, colorectal cancer, and other solid tumors in combination with chemotherapy or PD-1, PD-L1, MEK, EGFR, or SHP2 inhibitors, while adagrasib, a therapeutic agent for the KRAS G12C gene mutation, is in clinical trials for non-small cell lung cancer, colorectal cancer, and other solid tumors in combination with PD-1, EGFR, SHP2, CDK4 / 6, and / or SOS1 inhibitors.
[0003] BH3-only proteins can promote or induce apoptosis by inhibiting apoptosis regulatory functions. Loss of ERK1 / 2 activity inhibits phosphorylation of BIM, one of the BH3-only proteins, and loss of ERK-mediated phosphorylation leads to BIM stabilization and increased BIM expression. However, BIM induction alone is not sufficient to cause extensive apoptosis because BIM is bound and inhibited by anti-apoptotic proteins, such as proteins in the BCL2 family. Therefore, BH3 analogs or BH3-only protein-inducing drugs that can inhibit the function of anti-apoptotic proteins cause strong apoptosis when used simultaneously with drugs that induce loss of ERK1 / 2 activity, and BIM induction caused by inhibition of ERK signaling is the cause of increased apoptosis.
[0004] Using the same principle, BH3 analogs and BH3-only protein-inducing drugs are being studied to enhance the potent anticancer effects associated with apoptosis when used concomitantly with KRAS G12C mutation therapeutics. Summary of the invention Technical Purpose
[0005] The present disclosure aims to provide a pharmaceutical composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, wherein the pharmaceutical composition comprises aripiprazole as an active ingredient.
[0006] Another object of the present disclosure is to provide a health functional food composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, wherein the health functional food composition comprises aripiprazole as an active ingredient.
[0007] Another object of the present disclosure is to provide a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0008] Another object of the present disclosure is to provide a health functional food composition for preventing or improving cancer, the health functional food composition comprising a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients. Technical Solution
[0009] To achieve the above objectives, the present disclosure provides a pharmaceutical composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, wherein the pharmaceutical composition comprises aripiprazole as an active ingredient.
[0010] In addition, the present disclosure provides a health functional food composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, wherein the health functional food composition comprises aripiprazole as an active ingredient.
[0011] In addition, the present disclosure provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0012] In addition, the present disclosure provides a health functional food composition for preventing or improving cancer, wherein the health functional food composition comprises a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients. Beneficial Effects
[0013] The present disclosure relates to a composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, the composition comprising aripiprazole as an active ingredient, and more specifically, to a composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, the composition being capable of treating cancer by acting as an anti-cancer effect enhancer of a KRAS G12C gene mutation therapeutic agent in co-treatment with aripiprazole. By co-administering an effective amount of aripiprazole according to the present disclosure with a KRASG12C gene mutation therapeutic agent, the composition can be used as an anti-cancer effect enhancer of a KRAS G12C gene mutation therapeutic agent due to its excellent effect in enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent (e.g., inducing apoptosis of cancer cells). BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 Shown are the results of characterization of the effect of aripiprazole treatment on NOXA protein expression in MIA PaCa-2 cells and NCI-H1373 cells.
[0015] Figure 2 A schematic diagram illustrating the effect of NOXA (one of the BH3-only proteins) expression on the anticancer efficacy of KRAS G12C gene mutation therapeutics is shown.
[0016] Figure 3 Shown are results of characterization of the effects of aripiprazole treatment alone or in combination with KRAS G12C mutation therapeutics on PARP cleavage in MIAPaCa-2 cells.
[0017] Figure 4 Shown are results of characterization of the effects of aripiprazole treatment alone or in combination with a KRAS G12C mutation therapeutic on PARP cleavage in NCI-H1373 cells. DETAILED DESCRIPTION
[0018] Hereinafter, the present disclosure will be described in more detail.
[0020] The present disclosure provides a pharmaceutical composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, wherein the pharmaceutical composition comprises aripiprazole as an active ingredient.
[0021] The KRAS G12C gene mutation therapeutic agent may be any one selected from the group consisting of sotorasib, adagrasib, GDC-6036 and JDQ-443, but is not limited thereto.
[0022] The cancer may be melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer, but is not limited thereto.
[0023] The pharmaceutical composition can induce PARP cleavage of cancer cells, or increase NOVA expression.
[0024] In another embodiment of the present disclosure, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of: suitable carriers, excipients, disintegrants, sweeteners, coating agents, bulking agents, lubricants, glydents, flavoring agents, antioxidants, buffers, antibacterial agents, diluents, dispersants, surfactants, binders and lubricants, which are conventionally used in the manufacture of pharmaceutical compositions. Specifically, for carrier, excipient and diluent, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talcum, magnesium stearate and mineral oil can be used, and the solid preparation for oral administration can include tablet, pill, acid agent (acids), granule and capsule, and these solid preparations can be prepared by mixing at least one excipient (for example starch, calcium carbonate, sucrose or lactose and gelatin) in the composition. Except simple excipient, lubricant, for example magnesium stearate and talcum can also be used. Oral liquid preparation can be suspension, liquid, emulsion and syrup, and except commonly used simple diluent (for example water and liquid paraffin), various excipients, for example wetting agent, sweetener, spices and preservative can also be contained. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents and suppositories. For non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil and esters for injection such as ethyl oleate can be used. As the base material of suppositories, Witepsol, macrogol, Tween 61, cocoa butter, laurin fat and glycerin gelatin can be used. According to an embodiment of the present disclosure, the pharmaceutical composition can be given to the subject in a conventional manner by intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhaled, local, rectal, oral, intraocular or intradermal routes. The dosage of the active ingredient according to the present disclosure may vary according to the condition and weight of the subject, the type and severity of the disease, the drug form, and the route and duration of administration, and may be appropriately selected by those skilled in the art, and the daily dosage may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg. It may be administered once a day or divided into multiple doses, but the scope of the present disclosure is not limited thereto.
[0026] In addition, the present disclosure provides a health functional food composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, wherein the health functional food composition comprises aripiprazole as an active ingredient.
[0027] Health functional food can contain various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents (such as synthetic flavoring agents and natural flavoring agents), coloring agents and thickeners (cheese and chocolate), pectin acid and its salt, alginate and its salt, organic acid, protective colloid thickener, pH regulator, stabilizer, preservative, glycerine, alcohol and the carbonating agent used in carbonated beverage. In addition, it can contain the pulp used to make natural fruit juice, synthetic fruit juice and vegetable drink. These ingredients can be used alone or in combination. In addition, health functional food composition can be in any form in meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, instant noodles, chewing gum, ice cream, soup, beverage, tea, functional water, beverage, alcohol and vitamin complex. In addition, health functional food can further include food additives, unless otherwise specified, by according to the general rules of the Korean Food Additives Codex approved by the Ministry of Food and Drug Safety (Ministry of Food and Drug Safety) and the standards and guidelines related to the corresponding items of the general test method, determine the applicability as "food additives". The items listed in the "Korean Food Additive Code" may include, for example, chemically synthesized compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sorghum pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, noodle alkali agents, preservatives, and tar colorants. Here, in the process of manufacturing health functional foods, the content of the active ingredient added to the food may be appropriately adjusted if necessary, and preferably, the active ingredient may be added so that it is contained in an amount of 1 to 90 parts by weight based on 100 parts by weight of the food.
[0029] In addition, the present disclosure provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0030] The KRAS G12C gene mutation therapeutic agent may be any one selected from the group consisting of sotorasib, adagrasib, GDC-6036 and JDQ-443, but is not limited thereto.
[0031] The cancer may be melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer, but is not limited thereto.
[0033] In addition, the present disclosure provides a health functional food composition for preventing or improving cancer, wherein the health functional food composition comprises a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
[0035] Hereinafter, the present disclosure will be described in detail by way of examples to help understand the present disclosure. However, the following examples are only intended to illustrate the contents of the present disclosure, but the scope of the present disclosure is not limited to the following examples. The embodiments of the present disclosure are provided to more fully illustrate the present disclosure to those of ordinary skill in the art. Example
[0036] <Example 1> Identification of the effect of aripiprazole on NOXA protein expression
[0037] To identify the effect of aripiprazole on NOXA protein expression in cancer cells, MIA PaCa-2 cells and NCI-H1373 cells were treated with aripiprazole. After 8 hours, proteins were extracted from the cells after washing with PBS, and the level of NOXA expression was examined by Western blotting.
[0038] As a result, according to Figure 1 , the expression of NOXA protein was increased by aripiprazole treatment, indicating that aripiprazole exhibited the effect of inducing NOXA protein expression.
[0040] <Example 2> Identification of the effect of aripiprazole on apoptosis induced by KRAS G12C gene mutation therapeutic agents
[0041] (1) MIA PaCa-2 cells
[0042] To identify the effect of aripiprazole on apoptosis induced by KRAS G12C gene mutation therapeutics in cancer cells, MIA PaCa-2 cells were treated with aripiprazole alone or in combination with KRAS G12C gene mutation therapeutics. After 24 hours, proteins were extracted from the cells after washing with PBS, and the extent of PARP cleavage was examined by Western blotting.
[0043] As a result, according to Figure 3, found that co-treatment with aripiprazole and a KRAS G12C gene mutation therapeutic agent showed a superior PARP cleavage induction effect than that observed with treatment with aripiprazole or a KRAS G12C gene mutation therapeutic agent alone.
[0045] (2) NCI-H1373 cells
[0046] To identify the effect of aripiprazole on apoptosis of cancer cells induced by KRAS G12C gene mutation therapeutics, NCI-H1373 cells were treated with aripiprazole alone or in combination with KRAS G12C gene mutation therapeutics. After 24 hours, proteins were extracted from the cells after washing with PBS, and the extent of PARP cleavage was examined by Western blotting.
[0047] As a result, according to Figure 4 , found that co-treatment with aripiprazole and a KRAS G12C gene mutation therapeutic agent showed a superior PARP cleavage induction effect than that observed with treatment with aripiprazole or a KRAS G12C gene mutation therapeutic agent alone.
[0049] The above description of the present disclosure is for illustrative purposes only, and those skilled in the art will understand that the present disclosure can be easily converted into other specific forms without changing the technical ideas or basic features of the present disclosure. Therefore, it should be understood that the above embodiments are illustrative in all aspects and not restrictive.
[0050] The scope of the present disclosure is expressed by the following claims, and the meaning and scope of the claims and any changes or modifications derived from equivalent concepts should be understood to be included in the scope of the present disclosure.
Claims
1. A pharmaceutical composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, the pharmaceutical composition comprising aripiprazole as an active ingredient.
2. The pharmaceutical composition according to claim 1, wherein The KRAS G12C gene mutation therapeutic agent is any one selected from the group consisting of sotolacib, adagraciib, GDC-6036 and JDQ-443.
3. The pharmaceutical composition according to claim 1, wherein The cancer is melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer.
4. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition induces PARP cleavage of cancer cells, or increases NOXA expression.
5. A health functional food composition for enhancing the anti-cancer effect of a KRAS G12C gene mutation therapeutic agent, the health functional food composition comprising aripiprazole as an active ingredient.
6. A pharmaceutical composition for preventing or treating cancer, comprising: a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.
7. The pharmaceutical composition according to claim 6, wherein The KRAS G12C gene mutation therapeutic agent is any one selected from the group consisting of sotolacib, adagraciib, GDC-6036 and JDQ-443.
8. The pharmaceutical composition according to claim 6, wherein The cancer is melanoma, breast cancer, lymphoma, brain tumor, brain cancer, colorectal cancer, prostate cancer, lung cancer, osteosarcoma, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, chronic leukemia or acute leukemia, bladder cancer, kidney cancer or liver cancer.
9. A health functional food composition for preventing or improving cancer, the health functional food composition comprising: a KRAS G12C gene mutation therapeutic agent or a pharmaceutically acceptable salt thereof, and aripiprazole or a pharmaceutically acceptable salt thereof as active ingredients.